USOO576.0032A United States Patent (19) 11 Patent Number: 5,760,032 Kitajima et al. 45) Date of Patent: Jun. 2, 1998

54) THIENYLAZOLE COMPOUND AND OTHER PUBLICATIONS THENOTRAZOLODIAZEPINE CO UND T. Tahara et al. "Syntheses and Structure-Activity Relation 75) Inventors: Hiroshi Kitajima; Syuji Ehara; ships of 6-Aryl-4H-s-triazolo3.4-cithieno23-e 14-di Hideaki Sato, all of Fukuoka; Minoru azepines" Arzneimittel Forschung Drug Research, vol. 28. Moriwaki, Osaka; Kenichi Onishi, 1978. Fukuoka, all of Japan Waiser, et al. J. Med. Chem. (1991). 34(3), 1209-21. G.N. Woodruff et al., "Cholecyst Antagonists". Annu. Rev. 73) Assignee: Yoshitomi Pharmaceutical Industries, Pharmacol. Toxicol., vol. 31, pp. 469-501, 1991. Ltd., Osaka, Japan J. Martinez et al., "Synthesis and Biological Activity of New Peptide Segments of Gastrin Exhibiting Gastrin Antagonist 21 Appl. No.: 750,025 Property". J. Med. Chem. vol. 27. pp. 1597-1601, 1984. 1. B.E. Evans, "Methods for Drug Discovery: Development of 22 PCT Filed: Jun. 1, 1995 Potent, Selective. Orally Effective Cholecystokinin Antago 86 PCT No.: PCT/JP95/01071 nists". J. Med. Chem., vol. 31, pp. 2235-2246, 1988. S371 Date: Nov. 22, 1996 Primary Examiner Mukund J. Shah Assistant Examiner-Bruck Kifle S 102(e) Date: Nov. 22, 1996 Attorney; Agent, or Firn-Wenderoth. Lind & Ponack 87 PCT Pub. No.: WO95/32964 57 ABSTRACT CT Pub. Date: Dec. 7, 1995 Thienylazole compounds (I) and thienotriazolodiazepine 30 Foreign Application Priority Data compounds (II) of the formulas

Jun. 1, 1994 (JP) Japan ...... 6-00889 (I) (51) Int. Cl...... A61K 31/55; CO7D 491/00; C07D 513/00; CO7D 515/00 52 U.S. Cl...... 514/220; 540/560 58) Field of Search ...... 540/560; 514/220 56) References Cited U.S. PATENT DOCUMENTS 4,094.984 6/1978 Weber et al...... 424/269 (II) 4,199.588 4/1980 Weber et al. . ... 424/267 5,190,939 3/1993 Rault et al...... 514/220 5,532,233 7/1996 Weber et al...... 514,219 FOREIGN PATENT DOCUMENTS 0 254 245 1/1988 European Pat. Off.. N 1 O 446 133 Al 9/1991 European Pat. Off. . 0 559 891 A1 9/1993 European Pat. Off.. (CH)-h-Y-2 O 661 284A1 7/1995 European Pat. Off.. R3 2 361 398 3/1978 France. 2405682 8/1974 Germany. wherein R' and R are hydrogen, halogen. C-C alkyl and 49-42669 4/1974 Japan. the like; -A=B- is -N=N- and the like; R and R' 49-61197 6/1974 Japan. are hydrogen, C-C alkyl and the like; Y is -NHCO E. S. " -NHCONH-, -NHCOO- and the like; Z' and Z are " apan . aryl, heteroaryland the like; Ar is halogen-substituted phe 50-5809850-89369 5/19757/1975 Japan. nyll and the like;la and m isis 0 or an integer off 1-5. 50-148385 11/1975 Japan. 55-105681 8/1980 Japan. The compounds of the present invention have CCKantago 55-105682 8/1980 Japan. nistic action and gastrin antagonistic action, particularly 57-45754 9/1982 Japan. potent antagonistic action against CCK-A receptor, and are 55-12434 4/1989 Japan. useful as agents for the prophylaxis and treatment of central 1-294676 11/1989 Japan. and peripheral nervous system diseases (e.g. anxiety, 3-2232902-281.81 10/19911/1990 Japan. schizophrenia, and the like) and digestive diseases (e.g., 5-155871 6/1993 Japan pancreatitis, gastric ulcer, enterelicosis, irritable bowel syn 599 960 6/1978 siteland drome, constipation, and the like). 602741 7/1978 Switzerland. 603660 8/1978 Switzerland. S Claims, No Drawings 5,760,032 1 2 THENYLAZOLE COMPOUND AND juice, promotion of insulin release, control of pepsinogen THENOTRAZOLODIAZEPINE COMPOUND secretion, gastric delay of emptying, stimulation of ileum movement, contraction of gallbladder, and the like. The TECHNICAL FIELD physiological activity of CCK via CCK-B receptor report edly includes suppression of feeling of hunger, control of The present invention relates to novel thienylazole com dopaminergic nerves, control of pain and pain relief with pounds and thienotriazolodiazepine compounds having morphine. acceleration of memory, and the like, and CCK-B cholecystokinin (hereinafter abbreviated as CCK) and gas receptor antagonist is useful for the treatment and prophy trin antagonistic activities, which are utilized in the medical laxis of gastric ulcer and enterelicosis, emesis. control of field. appetite, pain, anxiety, dementia, schizophrenia, and the O like. BACKGROUND ART Mainly in experimental studies of pancreatitis in recent There have been heretofore reported a 2-thienyltriazole years, the involvement of CCK in the onset, evolution and aggravation of pancreatitis has been reported. Pancreatitis is compound (Japanese Patent Examined Publication No. a symptom wherein pancreatic tissues are digested by the 12434/1980) showing action on the central nervous system, 15 such as anti-convulsion activity and sedative activity; a enzyme secreted by the pancreas itself (autodigestion), and thienotriazolodiazepine compound (Japanese Patent Unex is mostly treated by pancreatic enzyme inhibitors such as a amined Publication No. 61197/1974) used as an antianxiety trypsin inhibitor. However, the therapeutic effects afforded drug; a 2-thienyltriazole compound (Japanese Patent Unex by them are not entirely satisfactory and a pharmaceutical amined Publication No. 69667/1974) used as an antianxiety agent exhibiting greater treatment effects has been desired. drug or an intermediate for pharmaceutical products; a Unlike other enzyme inhibitors, the CCK-A receptor antago 2-thienyltriazole compound (Japanese Patent Unexamined nist suppresses secretion of pancreatic enzyme itself and is Publication No. 58098/1975) which is an intermediate for a useful as a new agent for the treatment and prophylaxis of thienotriazolopyridine compound used as an antiinflamma pancreatitis. It is also effective for the treatment and pro tory drug, an antipyretic analgesic and the like; a phylaxis of gallbladder disorders, irritable bowel syndrome, 2-thienylimidazole compound (Japanese Patent Unexam 25 gastric ulcer, enterelicosis, emesis, pancreatic malignant ined Publication No. 893.69/1975) which has central muscle tumor, constipation and the like. relaxing activity, antianxiety activity and the like; a As a review on physiological activity of CCK and thera 2-thienyltriazole compound (Japanese Patent Examined peutic usefulness of CCK antagonists, there is known, for example, Annu. Rev. Pharmacol. Toxicol., Vol. 31, p. 469 Publication No. 45754/1982) used as a starting compound of 30 (1991). A compound having a CCK-A antagonistic activity, a pharmaceutical product such as an antianxiety drug; a such as proglumide, is reported in J. Med. Chem. Vol. 27, 2-thienyltriazole compound (Japanese Patent Unexamined p. 1597 (1984); a benzodiazepine compound, which is Publication No. 10568 1/1980) which is used as an anti typically devazepide 3(S)-1,3-dihydro-3-(2- anxiety drug; a 2-thienylimidazole compound (Japanese indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4- Patent Unexamined Publication No. 105682/1980) which is 35 benzodiazepin-2-one). is reported in J. Med. Chem. Vol. 31, used as an antianxiety drug; a 2-thienylazole compound p. 2235 (1988); and a 2-acylamino-5-thiazole derivative is (Japanese Patent Unexamined Publication No. 294676/ reported in Japanese Patent Unexamined Publication No. 1989) having calmodulin antagonistic activity, coronary and 155871/1993. However, these compounds are not satisfac cerebral vasodilating activities and PAF antagonistic activ tory from the aspects of the level of activity in vitro or in ity; and the like. vivo, selectivity for CCK-A receptor, physicochemical prop In addition, Japanese Patent Unexamined Publication No. erties (e.g., solubility in water), bioavailability, safety and 102698/1974 discloses that a thienotriazolodiazepine com pound which may be substituted by the like, alkoxycarbonylaminoalkyl, alkylcarbonyloxyalkyl and the DISCLOSURE OF THE INVENTION like at the 9-position thereof can be used as a tranquilizer or 45 The present inventors conducted intensive studies with an antianxiety drug. Japanese Patent Unexamined Publica the aim of providing a useful compound which serves well tion Nos. 28.181/1990 and 223290/1991 disclose thienotria for the treatment and prophylaxis of various diseases caused Zolodiazepine compounds having cholecystokinin antago by peripheral CCK, by the action of selectively blocking the mistic activity, which have, at the 6-position thereof, an binding to CCK-A receptor, and found that certain thieny amide substituent (e.g., indole-2-carboxamide) or ureido 50 lazole compounds and thienotriazolodiazepine compounds substituent (e.g., (3-(3methylphenyl)ureidol, which sub can achieve the object, which resulted in the completion of stituent being considered to be essential for the expression of the present invention. Accordingly, the present invention cholecystokinin antagonistic activity. provides the following. The cholecystokinin (also referred to as CCK) is a neu (1) Thienylazole compounds of the formula ropeptide consisting of 33 amino acids, and CCK-8 which 55 consists of 8 amino acids at the C terminus also shows activity. The gastrin consists of 34 amino acids, and penta gastrin which consists of 5 amino acids at the C terminus also shows activity. The amino acid sequence of the penta gastrin is identical to that at the C terminus of CCK. There have been reported different subtypes of CCK receptors which are generally classified into CCK-A receptor distrib uted in peripheral tissues such as pancreas and gallbladder, and CCK-B receptor distributed in the central nervous system. It is considered that CCK-B receptor and gastrin 65 wherein receptor are the same. The physiological activity of CCK via R" is a hydrogen, a halogen or an alkyl having 1 to 5 CCK-A receptor reportedly includes secretion of pancreatic carbon atoms(s); 5,760,032 3 4 R’ is a hydrogen, a halogen, a cyano, an alkyl having 1 to a group of the formula: 5 carbon atom(s), a cycloalkyl having 3 to 7 carbon atoms, an alkyl having 1 to 5 carbon atom(s) which is substituted by 1 to 3 hydroxyl group(s), an alkyl having 1 to 5 carbon atom(s) which is substituted by 1 to 3 wherein n is 0 or an integer of 1-5, and R7 and R' amino group(s), an alkanoyl having 2 to 5 carbon are the same or different and each is hydrogen or atoms, a phenylalkyl wherein phenyl ring is substituted alkyl having 1 to 5 carbon atom(s), or R'' and R' by alkyl having 1 to 5 carbon atom(s), a group of the in combination optionally form, together with the formula: adjacent nitrogen atom, a hetero ring, a group of the formula: -(CH)nCOOR -(CH)nCON(R) (R) wherein n is 0 or an integer of 1-5 and R' is hydrogen, wherein n is 0 or an integer of 1-5, and RandR alkyl having 1 to 5 carbon atom(s) or aralkyl. are the same or different and each is hydrogen or a group of the formula: 15 alkyl having 1 to 5 carbon atom(s), or R' and R' in combination optionally form, together with the -(CH)nCONGR) (R) adjacent nitrogen atom, a hetero ring, or wherein n is 0 or an integer of 1-5, and Rand R' a group of the formula: are the same or different and each is hydrogen o alkyl having 1 to 5 carbon atom(s), or RandR in combination optionally form, together with the adja cent nitrogen atom, a hetero ring, wherein n is 0 or an integer of 1-5, and R’ is a group of the formula: 5-tetrazolyl;

25 wherein p is 0, 1 or 2 and R' is arylor a heterocyclic wherein R is hydrogen, halogen, alkyl having 1 to group, 5 carbon atom(s), alkoxy having 1 to 5 carbon a group of the formula: atom(s), alkyl having 1 to 5 carbon atom(s) which is substituted by 1 to 3 hydroxyl group(s), alkanoyl 30 having 2 to 5 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, haloalkyl having 1 or 2 carbon wherein q is 1 or 2 and R’ is aryl or a heterocyclic atom(s), alkenyl, alkynyl, cycloalkylalkyl, aryl, group, or heteroaryl, aralkyl, heteroarylalkyl, aryloxyalkyl, a group of the formula: adamanty, adamantylmethyl, bicyclo group, a group 35 of the formula: wherein n is 0 or an integer of 1-5, and R is -(CH)nCOOR 5-tetrazolyl; or wherein n is 0 or an integer of 1-5, and R is R" and R combinedly form a ring optionally having a hydrogen, alkyl having 1 to 5 carbon atom(s) or group of the formula: aralkyl, -(CH)nCONCR) (R) a group of the formula: wherein n is 0 or an integer of 1-5, and RandR are -(CH)nCONCR) (R) the same or different and each is hydrogen or alkyl 45 wherein n is 0 or an integer of 1-5, and R and R' having 1 to 5 carbon atom(s), or R and R in are the same or different and each is hydrogen or combination optionally form, together with the adja alkyl having 1 to 5 carbon atom(s), or RandR' in cent nitrogen atom, a hetero ring; or combination optionally form, together with the adja R" and R' combinedly form a group of the formula cent nitrogen atom, a hetero ring, or a group of the 50 formula: -(CHnN(R) (R) whereinn is 0 or an integer of 1-5, and R'' and R' are the same or different and each is hydrogen or wherein r is 1 or 2, and R is cycloalkyl having 3 to 7 55 alkyl having 1 to 5 carbon atom(s), or R' and R' in carbon atoms; combination optionally form, together with the adja R is a hydrogen, an alkyl having 1 to 5 carbon atom(s). cent nitrogen atom, a hetero ring; an alkyl having 1 to 5 carbon atom(s) which is substi Y is -NHCO-, -NHCONH-., -NHCSNH tuted by 1 to 3 hydroxyl group(s), an aralkyl optionally -NHSO-, -NHCOO-, -OCONH-,-OCO substituted by 1 to 3 hydroxyl group(s) on an aromatic --NH CONHCO- -NHCSN H CO. ring, a heteroarylalkyl, a group of the formula: -NHCONHSO-, -NHCSNHSO - or -NHCOCONH-; -(CH)nCOOR." Z' is an alkyl having 1 to 5 carbon atom(s), an alkenyl, an wherein n is 0 or an integer of 1-5, and R' is 65 alkynyl, a cycloalkyl having 3 to 7 carbon atoms, a hydrogen, alkyl having 1 to 5 carbon atom(s), cycloalkylalkyl, an aralkyl, an aryl, a heteroaryl, a cycloalkyl having 3 to 7 carbon atoms or aralkyl, heteroarylalkyl, or a group of the formula: 5,760,032 6 (6) Thienotriazolodiazepine compounds of the formula wherein R" is cycloalkyl having 3 to 7 carbon atoms, Air (II) aryl or heteroaryl. R1 N wherein these rings are optionally substituted by an R19 optional number of substituent(s) selected from the group consisting of halogen, hydroxyl group, amino, R S N W N nitro, alkyl having 1 to 5 carbon atom(s), alkyl having N 1 1 to 5 carbon atom(s) which is substituted by 1 to 3 10 hydroxyl group(s), alkanoyl having 2 to 5 carbon (CH2)-CH-Y-Z2 atoms, haloalkyl having 1 or 2 carbon atom(s), alkoxy k having 1 to 5 carbon atom(s), alkylthio having 1 to 5 carbon atom(s), aryloxy, a group of the formula: wherein 15 R" is a hydrogen, a halogen or an alkyl having 1 to 5 -(CH)nCOOR carbon atom(s); R’ is a hydrogen, a halogen, a cyano, an alkyl having 1 to wherein n is 0 or an integer of 1-5, and R' is 5 carbon atom(s), a cycloalkyl having 3 to 7 carbon hydrogen, alkyl having 1 to 5 carbon atom(s) or aralkyl, atoms, an alkyl having 1 to 5 carbon atom(s) which is a group of the formula: substituted by 1 to 3 hydroxyl group(s), an alkyl having 1 to 5 carbon atom(s) which is substituted by 1 to 3 -(CH,)nCONCR) (R) amino group(s), an alkanoyl having 2 to 5 carbon atoms, a phenylalkyl wherein phenyl ring is substituted by alkyl having 1 to 5 carbon atom(s), a group of the wherein n is 0 or an integer of 1-5. and R' and R' 25 are the same or different and each is hydrogen or formula: alkyl having 1 to 5 carbon atom(s), or R' and R' in combination optionally form, together with the -(CH)nCOOR' adjacent nitrogen atom, a hetero ring, wherein n is 0 or an integer of 1-5 and R' is hydrogen, a group of the formula: alkyl having 1 to 5 carbon atom(s) or aralkyl, -(CH)nN(R7) (R) a group of the formula: whereinn is 0 or an integer of 1-5, and R'' and R' -(CH)nCONCR) (R') are the same or different and each is hydrogen or 35 wherein n is 0 or an integer of 1-5, and R and R' alkyl having 1 to 5 carbon atom(s), or R'' and R' are the same or different and each is hydrogen or in combination optionally form, together with the alkyl having 1 to 5 carbon atom(s), or RandR in adjacent nitrogen atom, a hetero ring, and combination optionally form, together with the adja a group of the formula: cent nitrogen atom, a hetero ring. a group of the formula: wherein n is 0 or an integer of 1-5, and R is 5-tetrazolyl; and wherein p is 0, 1 or 2 and R' is aryl or a heterocyclic Ar is a phenyl, a pyridyl, a thienyl, or a phenyl, pyridyl or 45 group. thienyl, having at least one substituent selected from a group of the formula: the group consisting of halogen, alkyl having 1 to 5 carbon atom(s), alkoxy having 1 to 5 carbon atom(s). haloalkyl having 1 or 2 carbon atom(s), alkylthio having 1 to 5 carbon atom(s), carboxyl. carboxyalkyl, 50 wherein q is 1 or 2 and R’ is aryl or heterocyclic nitro, amino and hydroxyl group, and pharmaceutically group, or acceptable salts thereof. a group of the formula: (2) Pharmaceutical compositions comprising the com pound of the above formula (I) or a pharmaceutically acceptable salt thereof in an amount effective for treatment, 55 and a pharmaceutically acceptable additive. wherein n is 0 or an integer of 1-5, and R' is (3) Agents for the treatment and prophylaxis of central 5-tetrazolyl; or nervous system diseases, which comprise the compound of R" and R combinedly form a ring optionally having a the above formula (I) or a pharmaceutically acceptable salt group of the formula: thereof. (4) Agents for the treatment and prophylaxis of peripheral -(CH)nCON(R') (R) nervous system diseases, which comprise the compound of the above formula (I) or a pharmaceutically acceptable salt wherein n is 0 or an integer of 1-5, and RandR are thereof. the same or different and each is hydrogen or alkyl (5) Agents for the treatment and prophylaxis of digestive 65 having 1 to 5 carbon atom(s), or R and R in diseases, which comprise the compound of the above for combination optionally form, together with the adja mula (I) or a pharmaceutically acceptable salt thereof. cent nitrogen atom, a hetero ring; or 5,760,032 7 R" and R combinedly form a group of the formula wherein R' is cycloalkyl having 3 to 7 carbon atoms, (h). aryl or heteroaryl. R23-CO-N wherein these rings are optionally substituted by an optional number of substituent(s) selected from the wherein r is 1 or 2. and R is cycloalkyl having 3 to 7 group consisting of halogen, hydroxyl group. amino, carbon atoms; nitro, alkyl having 1 to 5 carbon atom(s), alkyl having R is a hydrogen, an alkyl having 1 to 5 carbon atom(s), 1 to 5 carbon atom(s) which is substituted by 1 to 3 an alkyl having 1 to 5 carbon atom(s) which is substi 10 hydroxyl group(s), alkanoyl having 2 to 5 carbon tuted by 1 to 3 hydroxyl group(s), an aralkyl optionally atoms, haloalkyl having 1 or 2 carbon atom(s), alkoxy substituted by 1 to 3 hydroxyl group(s) on an aromatic having 1 to 5 carbon atom(s), alkylthio having 1 to 5 ring, a heteroarylalkyl, a group of the formula: carbon atom(s), aryloxy, a group of the formula: -(CH)nCOOR' 15 -(CH)nCOOR' whereinn is 0 or an integer of 1-5, and R' is hydrogen, wherein n is 0 or an integer of 1-5, and R' is alkyl having 1 to 5 carbon atom(s), cycloalkyl having hydrogen, alkyl having 1 to 5 carbon atom(s) or aralkyl, 3 to 7 carbon atoms or aralkyl, a group of the formula: a group of the formula: -(CH)nCON(R) (R') wherein n is 0 or an integer of 1-5, and R' and R' whereinn is 0 or an integer of 1-5, and R'' and R' are the same or different and each is hydrogen or are the same or different and each is hydrogen or alkyl having 1 to 5 carbon atom(s), or R' and R' alkyl having 1 to 5 carbon atom(s), or R'' and R' 25 in combination optionally form, together with the in combination optionally form, together with the adjacent nitrogen atom, a hetero ring. adjacent nitrogen atom, a hetero ring, a group of the formula: a group of the formula: -(CH)nN(R7) (R) -(CH)nCONGR) (R) whereinn is 0 or an integer of 1-5, and R'' and R' wherein n is 0 or an integer of 1-5, and RandR are the same or different and each is hydrogen or are the same or different and each is hydrogen or alkyl having 1 to 5 carbon atom(s), or R'' and R' alkyl having 1 to 5 carbon atom(s), or R and R' in combination optionally form, together with the in combination optionally form, together with the 35 adjacent nitrogen atom, a hetero ring, and adjacent nitrogen atom, a hetero ring, or a group of the formula: a group of the formula: wherein n is 0 or an integer of 1-5, and R is wherein n is 0 or an integer of 1-5, and R' is 5-tetrazolyl; and 5-tetrazolyl; Ar is a phenyl, a pyridyl, a thienyl, or a phenyl, pyridyl or thienyl, having at least one substituent selected from R" is a hydrogen, an alkyl having 1 to 5 carbon atom(s), the group consisting of halogen, alkyl having 1 to 5 a group of the formula: carbon atom(s), alkoxy having 1 to 5 carbon atom(s), -(CH)nCOOR' 45 haloalkyl having 1 or 2 carbon atom(s), alkylthio having 1 to 5 carbon atom(s), carboxyl, carboxyalkyl, wherein n is 0 or an integer of 1-5, and R' is nitro, amino and hydroxyl group, and hydrogen. alkyl having 1 to 5 carbon atom(s) or aralkyl, pharmaceutically acceptable salts thereof. O (7) Pharmaceutical compositions comprising the com a group of the formula: 50 pound of the above formula (DI) or a pharmaceutically acceptable salt thereof in an amount effective for treatment, and a pharmaceutically acceptable additive. (8) Agents for the treatment and prophylaxis of central whereinn is 0 or an integer of 1-5, and R'' and R' nervous system diseases, which comprise the compound of are the same or different and each is hydrogen or 55 the above formula (II) or a pharmaceutically acceptable salt alkyl having 1 to 5 carbon atom(s), or R'' and R' thereof. in combination optionally form, together with the (9) Agents for the treatment and prophylaxis of peripheral adjacent nitrogen atom, a hetero ring; nervous system diseases, which comprise the compound of m is 0 or an integer of 1-5; the above formula (II) or a pharmaceutically acceptable salt Y is --NHCO-, -NHCONH-, -NHCSNH-, thereof. -NHSO-, -NHCOO-, -OCONH-,-OCO-, (10) Agents for the treatment and prophylaxis of digestive -NH CONHCO- --NH CSNH CO diseases, which comprise the compound of the above for -NHCONHSO-, -NHCSN HSO2- or mula (DI) or a pharmaceutically acceptable salt thereof. -NHCOCONH-: In the above definition and the present specification. Z is an alkenyl, an alkynyl, a cycloalkyl having 3 to 7 65 halogen means chlorine, bromine, fluorine and iodine. carbon atoms, a cycloalkylalkyl, an aralkyl, an aryl, a Alkyl having 1 to 5 carbon atoms is straight or branched heteroaryl, a heteroarylalkyl or a group of the formula: chain alkyl, and exemplified by methyl, ethyl, propyl. 5,760,032 10 isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopenty and fied by indolylmethyl, pyridylmethyl, quinolylmethyl. the like, with preference given to methyl, ethyl and isopro thienylmethyl, furylmethyl and the like. Aryloxyalkyl is pyl. Alkoxy having 1 to 5 carbon atoms is straight or exemplified by phenoxymethyl 2-phenoxyethyl. branched chain alkoxy, and exemplified by methoxy, ethoxy, 3-phenoxypropyl, 4-phenoxybutyl and the like. propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, Each group of the formula (I) is preferably as follows: R' pentyloxy, isopentyloxy and the like, with preference given is hydrogen, halogen or alkyl having 1 to 5 carbon atoms; R’ to methoxy and ethoxy. Particularly preferred is methoxy. is hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkyl Haloalkyl having 1 or 2 carbon atoms is exemplified by having 1 to 5 carbon atoms which is substituted by 1 to 3 chloromethyl, fluoromethyl, difluoromethyl, hydroxyl groups, alkanoyl having 2 to 5 carbon atoms, trifluoromethyl, 2.2.2-trichloroethyl, 2.2.2-trifluoroethyl and 10 phenylalkyl wherein phenyl ring is substituted by alkyl the like, with preference given to trifluoromethyl. Alkylthio having 1 to 5 carbon atoms, a group of the formula: having 1 to 5 carbon atoms is straight or branched chain alkylthio, and exemplified by methylthio, ethylthio, -(CH)nCOOR propylthio, isopropylthio, butylthio, isobutylthio, tert wherein n is 0 or an integer of 1-5 and R' is hydrogen, alkyl butylthio. pentylthio, isopentylthio and the like, with pref 15 erence given to methylthio. Carboxyalkyl is exemplified by having 1 to 5 carbon atoms or aralkyl, a group of the carboxymethyl 2-carboxyethyl and the like, with preference formula: given to carboxymethyl. -(CH)nCONCR) (R) Aralkyl is exemplified by benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl and the like. Preferred is wherein n is 0 or an integer of 1-5, and R and Rare the benzyl. Cycloalkyl having 3 to 7 carbon atoms is exempli same or different and each is hydrogen or alkyl having 1 to fied by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 carbon atoms, or R and R in combination optionally cycloheptyl and the like, with preference given to that form, together with the adjacent nitrogen atom, a hetero ring, having 3 to 6 carbon atoms. Particularly preferred are a group of the formula cyclopropyl and cyclohexyl. Aryl is exemplified by phenyl, 25 naphthyl and the like, with preference given to phenyl. Aryloxy is exemplified by phenoxy, 1-naphthyloxy, wherein p is 0, 1 or 2 and R' is aryl or heterocyclic group. 2-naphthyloxy and the like, with preference given to phe or a group of the formula noxy. Alkyl having 1 to 5 carbon atoms which is substituted by 1 to 3 hydroxyl groups is exemplified by hydroxymethyl, 30 1-hydroxyethyl 2-hydroxyethyl 3-hydroxypropyl, 4-hydroxybutyl and the like, with preference given to wherein q is 1 or 2 and R’ is aryl or heterocyclic group; or hydroxymethyl. Alkanoyl having 2 to 5 carbon atoms is R" and R' combinedly form a ring, which optionally has exemplified by acetyl, propionyl, butyryl, valleryl, pivaloyl a group of the formula: and the like, with preference given to acetyl. Phenylalkyl 35 wherein phenyl ring is substituted by alkyl having 1 to 5 -(CH)nCONCR) (R) carbon atoms is exemplified by 2-(4-isobutylphenyl)ethyl, wherein n is 0 or an integer of 1-5, and R and Rare the 2-(4-butylphenyl)ethyl and the like, with preference given to same or different and each is hydrogen or alkyl having 1 to 2-(4-isobutylphenyl)ethyl. Hetero ring which is formed 5 carbon atoms, or R and R in combination optionally together with the adjacent nitrogen atom is exemplified by form, together with the adjacent nitrogen atom, hetero ring, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-piperazinyl 4-methyl-1-piperazinyl, 1-azepinyl, O morpholino, thiomorpholino. 4-methylpipreidino, R" and R combinedly form a group of the formula phthalimide, succinimide and the like. Heteroaryl is exem plified by pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, 45 (h). oxazolyl, isoxazolyl, thiazolyl pyridazinyl, pyrimidinyl, R23-CO-N pyrazinyl, indolyl. indolinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolyl. isoquinolyl, wherein r is 1 or 2, and R’ is cycloalkyl having 3 to 7 quinoxalinyl, quinazolinyl and the like. Preferred are 50 carbon atoms; R is hydrogen, alkyl having 1 to 5 carbon 3-quinolyl. 2-benzofuranyl, 2,3-dihydro-7-benzofuranyl, atoms, a group of the formula: 2-benzothienyl 2-indolyl, 2-indolinyl and the like, and particularly preferred is 2-indolyl. The ring which is com -(CH)nCOOR' binedly formed by R' and R means cyclopentene ring, wherein n is 0 or an integer of 1-5, and R' is hydrogen, cyclopentadiene ring, cyclohexene ring, cyclohexadiene 55 ring, benzene ring, cycloheptene ring, cycloheptadiene ring. alkyl having 1 to 5 carbon atoms or aralkyl, or a group of the cycloheptatriene ring and the like, with preference given to formula: cyclohexene ring. The heterocyclic group is exemplified by pyridyl, imidazolyl, thienyl, furyl, pyrimidinyl, oxazolyl and the like. wherein n is 0 or an integer of 1-5, and R'' and R' are the Alkenyl is that having 2 to 6 carbon atoms, which is same or different and each is hydrogen or alkyl having 1 to exemplified by vinyl, propenyl, 2-methyl-1-propenyl, 5 carbon atoms, or R'' and R' in combination optionally 1-butenyl, 3-butenyl, 3-hexenyl and the like. Alkynyl is form, together with the adjacent nitrogen atom, hetero ring; exemplified by ethynyl, 1-propynyl, propargyll, 3-hexynyl and the like. Cycloalkylalkyl is exemplified by 65 cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, wherein R is hydrogen. halogen. alkyl having 1 to 5 carbon cyclohexylmethyl and the like. Heteroarylalkyl is exempli atoms, alkyl having 1 to 5 carbon atoms which is substituted 5,760,032 11 12 by 1 to 3 hydroxyl groups, alkanoyl having 2 to 5 carbon 1 to 5 carbon atoms, or R'' and R' in combination atoms, cycloalkyl having 3 to 7 carbon atoms, haloalkyl optionally form, together with the adjacent nitrogen atom, having 1 or 2 carbon atoms, alkenyl. alkynyl, hetero ring; and cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, Ar is phenyl, pyridyl, thienyl, or phenyl, pyridyl or aryloxyalkyl, adamantyl, adamantylmethyl, bicyclo group, a thienyl, having at least one substituent selected from group of the formula: the group consisting of halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, -(CH)nCOOR' haloalkyl having 1 or 2 carbon atoms, alkylthio having wherein n is 0 or an integer of 1-5, and R is hydrogen, alkyl 1 to 5 carbon atoms, carboxyl, carboxyalkyl. nitro. having 1 to 5 carbon atoms or aralkyl, a group of the 10 amino and hydroxyl group. formula: Each group of the formula (I) is more preferably as follows: R" is hydrogen or alkyl having 1 or 2 carbon atoms; -(CH)nCONCR) (R') 15 R’ is alkyl having 1 to 3 carbon atoms, cycloalkyl having wherein n is 0 or an integer of 1-5, and R and R' are the 3 to 7 carbon atoms, -(CH)nCOOR wherein n is 0 same or different and each is hydrogen or alkyl having 1 to or 1 and R' is hydrogen or alkyl having 1 to 4 carbon 5 carbon atoms, or R and R' in combination optionally atoms, or 5-tetrazolyl; form, together with the adjacent nitrogen atom, hetero ring, R is hydrogen or -(CH2)ncOOR' wherein n is an or a group of the formula: 20 integer of 1-4, and R' is hydrogen, cyclohexyl or benzyl; -(CHnN(R) (R') -A= B - is -N=N-, -CH=CH- or wherein n is 0 or an integer of 1-5, and R' and R'' are the -C(R)=N- wherein R is hydrogen, halogen. alkyl same or different and each is hydrogen or alkyl having 1 to having 1 to 4 carbon atoms, alkyl having 1 or 2 carbon 5 carbon atoms, or R' and R' in combination optionally 25 atoms which is substituted by one hydroxyl group, form, together with the adjacent nitrogen atom, hetero ring; cyclohexyl, trifluoromethyl, -(CH)nCOOR wherein Y is - NHCO-, -NHCONH-, -NHCSNH n is 0, 1 or 2, and R is hydrogen or alkyl having 1 or -NHSO-, -NHCOO--OCONH-,-OCO 2 carbon atoms, or -(CH)nN(R') (R') wherein n is -NH CONHCO- -NHCSNHCO 1. and R'' and R'' are the same or different and each -NHCONHSO-, -NHCSNHSO - or is alkyl having 1 or 2 carbon atoms; - NHCOCONH-; Y is --NHCO-, --NHCONH- - -NHCSNH-, Z" is alkyl having 1 to 5 carbon atoms, alkenyl, alkynyl, -NHSO-, -OCONH- or -OCO cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl, Z' is aryl, heteroaryl or -CH=CH-R" wherein R' is aralkyl, aryl. heteroaryl, heteroarylalkyl, or a group of 35 phenyl, wherein these rings may have 1 or 2 substitu the formula: ents selected from the group consisting of halogen, amino, nitro, methyl, methoxy, -(CH)nCOOR' wherein n is 0 or an integer of 1-4, and R' is hydrogen or alkyl having 1 to 4 carbon atoms, and wherein R' is cycloalkyl having 3 to 7 carbon atoms, aryl 1H-tetrazol-5-ylmethyl; and Ar is phenyl or phenyl or heteroaryl, wherein these rings in the definition of Z' are having halogen on the ring. optionally substituted by an optional number of substituent Each group of the formula (I) is still more preferably as (s) selected from the group consisting of halogen, hydroxyl follows: group, amino, nitro, alkyl having 1 to 5 carbon atoms, alkyl R" is hydrogen; R is alkyl having 1 to 3 carbon atoms, having 1 to 5 carbon atoms which is substituted by 1 to 3 45 cycloalkyl having 3 to 6 carbon atoms or -(CH2) hydroxyl groups, alkanoyl having 2 to 5 carbon atoms, nCOOH whereinn is 0 or 1; R is hydrogen;-A=B- haloalkyl having 1 or 2 carbon atoms. alkoxy having 1 to 5 is -C(R)=N- wherein R is halogen, carbon atoms, alkylthio having 1 to 5 carbon atoms, aryloxy, trifluoromethyl, 1-adamantyl, alkyl having 1 to 4 car a group of the formula: bon atoms or cyclohexyl; Y is -NHCO- or -(CH)nCOOR SO -NHCONH-; Z is phenyl or heteroaryl, wherein these rings may have 1 or 2 substituents selected from wherein n is 0 or an integer of 1-5, and R' is hydrogen, the group consisting of halogen, amino, methyl, alkyl having 1 to 5 carbon atoms or aralkyl, a group of the methoxy, 1H-tetrazol-5-ylmethyl and -(CH2)nCOOH formula: wherein n is an integer of 1 to 3; and Ar is phenyl 55 having halogen on the ring. -(CH)nCON(R) (R) Heteroaryl at Z is exemplified by the following. wherein n is 0 or an integer of 1-5, and R' and R'' are the same or different and each is hydrogen or alkyl having 1 to 5 carbon atoms, or R' and R' in combination optionally form, together with the adjacent nitrogen atom, hetero ring, and a group of the formula:

65 wherein n is 0 or an integer of 1-5, and R'' and R' are the same or different and each is hydrogen or alkyl having

5,760,032 1S 16 (374) (3-(2-chlorobenzoyl)-2-(3-(3-(3-chlorophenyl) 5 carbon atoms, or R'' and R' in combination optionally ureidomethyl)-5-methyl(1,2,4-triazol-4-yl)thiophen-5-yl) form, together with the adjacent nitrogen atom, hetero ring; carboxylic acid. R" is hydrogen, alkyl having 1 to 5 carbon atoms, a group (253) (3-(2-chlorobenzoyl)-2-(3-(3-(2-chlorophenyl) of the formula ureidomethyl)-5-methyl 12.4 triazol-4-yl)thiophen-5-yl) carboxylic acid, -(CH)nCOOR' (251) (3-(2-chlorobenzoyl)-2-(3-(3,4- dichlorobenzoylaminomethyl)-5-methyl(1,2,4-triazol-4- wherein n is 0 or an integer of 1-5, and R' is hydrogen, yl)thiophen-5-yl)carboxylic acid. alkyl having 1 to 5 carbon atoms or aralkyl, or a group of the Each group of the formula (II) is preferably as follows: 10 formula R" is hydrogen, halogen or alkyl having 1 to 5 carbon -(CH)nN(R7) (R) atoms; R’ is hydrogen, halogen, alkyl having 1 to 5 carbon wherein n is 0 or an integer of 1-5, and R'' and R' are atoms, alkyl having 1 to 5 carbon atoms which substi the same or different and each is hydrogen or alkyl having tuted by 1 to 3 hydroxyl groups, alkanoyl having 2 to 15 1 to 5 carbon atoms, or R'' and R' in combination 5 carbon atoms, phenylalkyl wherein phenyl ring is optionally form, together with the adjacent nitrogen atom, substituted by alkyl having 1 to 5 carbon atoms, a group hetero ring; of the formula m is 0 or an integer of 1-5; 20 Y is -NHCO-, -NHCONH-, -NHCSNH -NHSO-, -NHCOO--OCONH--OCO wherein n is 0 or an integer of 1-5 and R' is hydrogen, alkyl -NH CONH CO- - N H CSN HCO having 1 to 5 carbon atoms or aralkyl, a group of the formula -NH CONHSO-, -NHCS NHSO - or --NHCOCONH -(CH)nCON(R) (R) 25 Z is alkenyl, alkynyl, cycloalkyl having 3 to 7 carbon wherein n is 0 or an integer of 1-5 and R and Rare the atoms, cycloalkylalkyl, aralkyl, aryl, heteroaryl, het same or different and each is hydrogen or alkyl having 1 to eroarylalkyl or a group of the formula 5 carbon atoms, or R and R in combination optionally form, together with the adjacent nitrogen atom, hetero ring. a group of the formula 30 wherein R' is cycloalkyl having 3 to 7 carbon atoms, aryl or heteroaryl, wherein these rings in the definition of Z are optionally substituted by an optional number of substituent wherein p is 0.1 or 2 and R' is aryl or heterocyclic group. (s) selected from the group consisting of halogen, hydroxyl or a group of the formula group, amino, nitro, alkyl having 1 to 5 carbon atoms, alkyl 35 having 1 to 5 carbon atoms which substituted by 1 to 3 hydroxyl groups, alkanoyl having 2 to 5 carbon atoms. wherein q is 1 or 2 and R’ is aryl or heterocyclic group; or haloalkyl having 1 or 2 carbon atoms, alkoxy having 1 to 5 R" and R combinedly form a ring, which optionally have a carbon atoms, alkylthio having 1 to 5 carbon atoms, aryloxy, group of the formula a group of the formula -(CH,ncoNOR) (R) -(CH)nCOOR' wherein n is 0 or an integer of 1-5, and R and Rare the wherein n is 0 or an integer of 1-5, and R' is hydrogen, same or different and each is hydrogen or alkyl having 1 to alkyl having 1 to 5 carbon atoms or aralkyl, a group of the 5 carbon atoms, or R' and R in combination optionally formula form, together with the adjacent nitrogen atom, hetero ring, 45 O -(CH)nCONGR) (R) R" and R' combinedly form a group of the formula wherein n is 0 or an integer of 1-5, and R' and R' are the same or different and each is hydrogen or alkyl having 1 to (H.), 5 carbon atoms, or R' and R' in combination optionally R23-CO-N form, together with the adjacent nitrogen atom. hetero ring. and a group of the formula wherein r is 1 or 2, and R is cycloalkyl having 3 to 7 55 carbon atoms; wherein n is 0 or an integer of 1-5, and R'' and R' are R is hydrogen, alkyl having 1 to 5 carbon atoms, a group the same or different and each is hydrogen or alkyl having of the formula 1 to 5 carbon atoms, or R'' and R' in combination optionally form, together with the adjacent nitrogen atom, -(CH)nCOOR' hetero ring; and wherein n is 0 or an integer of 1-5, and R' is hydrogen, Ar is phenyl, pyridyl, thienyl, or phenyl, pyridyl or alkyl having 1 to 5 carbon atoms or aralkyl, or a group of the thienyl, which have at least one substituent selected formula from the group consisting of halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, 65 haloalkyl having 1 or 2 carbon atoms, alkylthio having wherein n is 0 or an integer of 1-5, and R'' and R' are the 1 to 5 carbon atoms, carboxyl, carboxyalkyl, nitro, same or different and each is hydrogen or alkyl having 1 to amino and hydroxyl group.

5,760,032 19 20 However, preferred are salts with an inorganic acid such as methylpyridinium iodide-tributylamine (Mukaiyama hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid method) in an inert solvent or without solvent, preferably at and hydrobromic acid, salts with an organic acid such as a temperature of from -20° C. to 80° C. These reactions acetic acid, propionic acid, succinic acid, glycolic acid, generally end in 24 hours. The inert solvent to be used in the lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, above-mentioned amidation is exemplified by hydrocarbons maleic acid, fumaric acid, methanesulfonic acid, benzene such as hexane, benzene, toluene and the like, halogenated sulfonic acid. p-toluenesulfonic acid and pamoic acid, salts hydrocarbons such as chloroform, dichloromethane, dichlo with an alkali metal such as lithium, sodium, potassium. roethane and the like, ethers such as tetrahydrofuran, diox calcium, magnesium and aluminium, salts with an organic ane and the like, esters such as acetate and the like, ketones base such as piperidine, pyrrollidine, piperazine, morpholine, 10 such as acetone, methyl ethyl ketone and the like, amides guanidine, dicyclohexylamine and N-methylglucamine, and such as dimethylformamide, dimethylacetamide and the salts with an amino acid Such as aspartic acid, glutamic acid, like, acetonitrile, dimethyl sulfoxide and water, and a mixed lysine and arginine. solvent thereof, which can be selected as appropriate accord When the compound of the present invention has an ing to the reaction. asymmetric center in a molecule, the present invention 15 Method I-2 encompasses optically pure enantiomorph, diastereomer and A compound of the formula (I) wherein Y is mixtures thereof. -NHCONH- is synthesized by reacting the amino com The production methods of the compounds of the present pound of the formula (1) or an acid addition salt thereof with invention of the formula (I) are shown in the following an isocyanate of the formula Method I-1 to Method I-15, to which the production meth ods are not limited. Method I-1 A compound of the formula (I) wherein Y is -NHCO wherein Z is as defined above. or by reacting an amino is synthesized by condensing an amino compound of the compound of the formula formula 25 HN-Z" (4)

wherein Z' is as defined above, with phosgene (e.g., trichlo (I) romethyl chloroformate and bis(trichloromethyl)carbonate) or carbonyldiimidazole, and then reacting the obtained reac 30 tion mixture with the amino compound of the formula (1) or an acid addition salt thereof. These reactions are carried out in the presence of an acid scavenger such as an organic base (e.g., triethylamine, SB 1. N-methylmorpholine, pyridine and dimethylaniline) or an 35 inorganic base (e.g., alkali hydrogencarbonate, alkali car wherein each symbol is as defined above, or an acid addition bonate and alkalihydroxide) as necessary without solvent or salt thereof and a carboxylic acid of the formula in an inert solvent, preferably at a temperature of from -20° C. to 80° C. The reactions generally end in 24 hours. The HOOC-2 (2) inert solvent to be used is exemplified by hydrocarbons such wherein each symbol is as defined above, or a reactive as hexane, benzene, toluene and the like, halogenated hydro derivative thereof. carbons such as chloroform, dichloromethane, dichloroet The above condensation can be carried out by a known hane and the like, ethers such as tetrahydrofuran, dioxane, method such as amidation, peptide synthesis and the like. diethyl ether, diisopropyl ether and the like, esters such as When the reactive derivative of carboxylic acid is an acid acetate and the like, ketones such as acetone, methyl ethyl halide (e.g., acid chloride and acid bromide) or acid anhy 45 ketone and the like, amides such as dimethylformamide, dride (e.g., symmetric acid anhydride, mixed anhydride with dimethylacetamide and the like. acetonitrile and dimethyl lower alkyl carbonate, and mixed anhydride with alkylphos sulfoxide, and a mixed solvent thereof, which can be phoric acid), the reaction is generally carried out in an inert selected as appropriate according to the reaction. solvent or without solvent, preferably in the presence of an Method I-3 acid scavenger such as an organic base (e.g., triethylamine, SO A compound of the formula (I) wherein Y is N-methylmorpholine, pyridine and dimethylaniline) or an -NHCSNH- is synthesized by reacting the amino com inorganic base (e.g. alkali hydrogencarbonate, alkali car pound of the formula (1) or an acid addition salt thereof and bonate and alkali hydroxide) at a temperature of from -20° an isothiocyanate of the formula C. to 80° C. When the reactive derivative is a lower alkyl ester (e.g., methyl ester and ethyl ester) or a so-called active 55 ester (e.g., 4-nitrophenyl ester, 4-chlorobenzyl ester, wherein Z' is as defined above. The reaction proceeds under 4-chlorophenyl ester, succinimide ester, benzotriazole ester the same conditions as in Method I-2. and 4-dimethylsulfoniumphenyl ester), the reaction is gen Method I-4 erally carried out in an inert solvent or without solvent at a A compound of the formula (I) wherein Y is -NHSO temperature of from -20°C. to the refluxing temperature of is synthesized by reacting the amino compound of the the solvent. Amidation of free carboxylic acid is carried out formula (1) or an acid addition salt thereof with a sulfonyl in the presence of a condensing agent such as carbodiimide halide of the formula (e.g., N,N-dicyclohexylcarbodiimide and 1-ethyl-3-(3- dimethylam in op ropyl)-car bodiimide, 2-SO-X" (6) diphenylphosphorylazide, carbonyldiimidazole, 65 wherein X" is a halogen such as chlorine, bromine and the 1-benzotriazolyloxytris(dimethylamino)phosphonium like, and Z' is as defined above, or with a sulfonic acid hexafluorophosphate (Bop reagent) and 2-chloro-N- anhydride of the formula 5,760,032 21 (Z-SO).O (7) (10) wherein Z' is as defined above. This amidation is carried out preferably in the presence of 5 an acid scavenger such as an organic base (e.g., triethylamine, N-methylmorpholine, pyridine and dimethylaniline) or an inorganic base (e.g., alkali N hydrogencarbonate, alkali carbonate and alkali hydroxide) without solvent or in an inert solvent, preferably at a O wherein each symbol is as defined above. temperature of from -20° C. to 80° C. These reactions The reaction generally proceeds with ease in the presence generally end in 24 hours. The inert solvent to be used is of hydrochloric acid, sulfuric acid, phosphoric acid, exemplified by hydrocarbons such as hexane, benzene, p-toluenesulfonic acid, methanesulfonic acid, camphorsul toluene and the like, halogenated hydrocarbons such as fonic acid and the like, in an aqueous solution or an organic chloroform, dichloromethane, dichloroethane and the like, 5 solvent containing water. The solvent to be used is exem ethers such as tetrahydrofuran, dioxane, diethyl ether, diiso plified by alcohols such as methanol, ethanol, isopropyl propyl ether and the like, esters such as acetate and the like, alcohol and the like, ethers such as tetrahydrofuran, dioxane ketones such as acetone, methyl ethyl ketone and the like, and the like, amides such as dimethylformamide, dimethy amides such as dimethylformamide, dimethylacetamide and acetamide and the like, and dimethyl sulfoxide. While the the like, acetonitrile and dimethyl sulfoxide, and a mixed 20 concentration of the acid and the reaction temperature solvent thereof, which can be selected as appropriate accord depend on stability of diazepine ring of the compound of the ing to the reaction. formula (10) to be used, the reaction is generally carried out for 30 minutes to several hours at a pH of not more than 5 Method I-5 at a temperature of from room temperature to the refluxing A compound of the formula (I) wherein Yis-NHCOO 25 temperature of the solvent. The obtained amino compound is is synthesized by reacting the amino compound of the separated as a suitable acid addition salt and can be used as formula (1) or an acid addition salt with a compound of the a starting compound, or can be subjected to the next prepa formula ration step without separation. Method I-7 30 A compound of the formula (I) wherein Yis-OCONH is synthesized by reacting a hydroxy compound of the formula wherein X* is a halogen such as chlorine, bromine and the (11) like, and Z' is as defined above, or with a compound of the 35 formula

(Z-OCO)O (9) wherein Z is as defined above. This amidation is carried out preferably in the presence of an acid scavenger such as an organic base (e.g., triethylamine, N-methylmorpholine, pyridine and wherein each symbol is as defined above, with the isocyan 45 ate of the formula (3), or by reacting the amino compound dimethylaniline) or an inorganic base (e.g., alkali of the formula (4) with phosgene (e.g., trichloromethyl hydrogencarbonate, alkali carbonate and alkali hydroxide) chloroformate and bis(trichloromethyl)carbonate) or without solvent or in an inert solvent, preferably at a carbonyldiimidazole, and reacting the obtained reaction temperature of from -20° C. to 80° C. These reactions mixture with the hydroxy compound of the formula (11) or generally end in 24 hours. The inert solvent to be used is 50 an acid addition salt thereof. exemplified by hydrocarbons such as hexane, benzene, These reactions are carried out in the presence of an acid toluene and the like, halogenated hydrocarbons such as scavenger such as an organic base (e.g., triethylamine, chloroform, dichloromethane, dichloroethane and the like. N-methylmorpholine, pyridine and dimethylaniline) or an ethers such as tetrahydrofuran, dioxane, diethyl ether, diiso inorganic base (e.g., alkali hydrogencarbonate, alkali car propyl ether and the like, esters such as acetate and the like, 55 bonate and alkalihydroxide) as necessary without solventor ketones such as acetone, methyl ethyl ketone and the like. in an inert solvent, preferably at a temperature of from -20° amides such as dimethylformamide, dimethylacetamide and C. to 80° C. The reactions generally end in 24 hours. The the like, acetonitrile and dimethyl sulfoxide, and a mixed inert solvent to be used is exemplified by hydrocarbons such solvent thereof, which can be selected as appropriate accord as hexane, benzene, toluene and the like. halogenated hydro ing to the reaction. carbons such as chloroform, dichloromethane, dichloroet Method I-6 hane and the like, ethers such as tetrahydrofuran, dioxane. diethyl ether, diisopropyl ether and the like, esters such as The amino compound of the formula (1) is easily acetate and the like, ketones such as acetone, methyl ethyl synthesized, for example, according to the method described ketone and the like, amides such as dimethylformamide, in Japanese Patent Unexamined Publication No. 36677/1974 65 dimethylacetamide and the like, acetonitrile and dimethyl by hydrolyzing, with an acidic aqueous solution, a thieno sulfoxide, and a mixed solvent thereof, which can be diazepine compound of the formula selected as appropriate according to the reaction. 5,760,032 23 Method I-8 (I-a) A compound of the formula (I) wherein Y is -OCO can be easily synthesized by a known esterification reaction of the carboxylic acid of the formula (2) or an acid halide thereof and the hydroxy compound of the formula (11). When an acid halide of the compound of the formula (2), such as acid chloride, acid bromide and the like. is used, the esterification is carried out in an inert solvent or without solvent, preferably at a temperature of from -20° C. to the boiling point of the solvent to be used. When a free car boxylic acid of the formula (2) is used, the esterification is wherein R is lower alkyl and other symbols are as defined carried out in the presence of a condensing agent such as 15 above. can be also obtained by hydrolysis of a compound of carbodiimide (e.g., N,N-dicyclohexylcarbodiimide and the formula 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) and carbonyldiimidazole, preferably at a temperature of from (12) -20° C. to 80° C. The esterification can be carried out in an inert solvent, preferably in the presence of an acid catalyst (e.g., hydrogen chloride, sulfuric acid and p-toluenesulfonic acid). The reaction may rapidly proceed by raising the reaction temperature to the boiling point of the solvent to evaporate the water produced. The inert solvent for the above-mentioned esterification is exemplified by hydrocar bons such as hexane, benzene, toluene and the like, halo genated hydrocarbons such as chloroform, dichloromethane, dichloroethane and the like, ethers such as tetrahydrofuran, wherein each symbol is as defined above, and then reacting dioxane, diethyl ether, diisopropyl ether and the like, esters 30 the obtained compound with an alkali metal nitrite. such as acetate and the like, ketones such as acetone and the The hydrolysis of the compound of the formula (12) like, dimethylformamide, dimethylacetamide, and dimethyl generally proceeds easily in an aqueous solution in the sulfoxide, and a mixed solvent thereof, which can be presence of hydrochloric acid, sulfuric acid, phosphoric selected as appropriate according to the reaction. 35 acid, p-toluenesulfonic acid, methanesulfonic acid and the like. While the concentration of the acid and the reaction Method I-9 temperature depend on stability of diazepine ring of the compound of the formula (12) to be used, the reaction is The hydroxy compound of the formula (11) can be generally carried out for 30 minutes to several hours at a pH obtained by hydrolyzing the thienodiazepine compound of of not more than 5 at a temperature of from room tempera the formula (10) and then reacting the obtained compound ture to the refluxing temperature of the solvent. Then, an with an alkali metal nitrite. alkali metal nitrite (e.g., sodium nitrite and potassium nitrite) is added to the reaction mixture, and the mixture is The hydrolysis of the compound of the formula (10) reacted at room temperature to under heating for several generally proceeds with ease in an aqueous solution in the 45 minutes to give the compound of the formula (I-a). presence of hydrochloric acid, sulfuric acid, phosphoric Method I-11 acid, p-toluenesulfonic acid, methanesulfonic acid and the A compound of the formula (I) wherein -A=B- is like. While the concentration of the acid and the reaction -C(R)=N- wherein R' is dimethylaminomethyl, can be temperature depend on stability of diazepine ring of the 50 also synthesized from the compound of the formula (II) of compound of the formula (10) to be used, the reaction is the present invention. For example, a compound of the generally carried out for 30 minutes to several hours at a pH formula of not more than 5 at a temperature of from room tempera ture to the refluxing temperature of the solvent. Then, an (I-b) alkali metal nitrite (e.g., sodium nitrite and potassium 55 nitrite) is added to the reaction mixture, and the mixture is reacted at a temperature of from room temperature to under heating for several minutes to give the compound of the formula (11). Method I-10

A compound of the formula (I) wherein -A=B- is wherein each symbol is as defined above, can be also -C(R)=N- wherein R is 1-hydroxyalkyl can be also 65 synthesized by reacting a compound of the following synthesized from the compound of the formula (II) of the formula, which is a compound of the formula (II) wherein m present invention. For example, a compound of the formula is 0 and R' is hydrogen, 5,760,032 26 wherein Z' is as defined above.

(13) The reaction proceeds under the same conditions as in Method I-2. Method I-16 A compound of the formula (I) wherein Y is -NHCOCONH- is synthesized by reacting the amino compound of the formula (4) or an acid addition salt thereof, 10 with oxalyl chloride in an inert solvent in the presence of an acid scavenger such as an organic base (e.g., triethylamine, N-methylmorpholine, pyridine and dimethylaniline) or an wherein each symbol is as defined above, with formic acid inorganic base (e.g., alkali hydrogencarbonate, alkali car and formaldehyde. bonate and alkali hydroxide) at room temperature or under The formic acid to be used may be one having a concen 15 ice-cooling, and then reacting the resulting reaction mixture tration of 60-90%. which is industrially available. Those with the amino compound of the formula (1) preferably at a having higher or lower concentrations may be also used. temperature of from -20° C. to room temperature. These Formaldehyde may be an aqueous solution or a solid such as reactions generally end in 24 hours. The inert solvent to be paraformaldehyde. The starting compound (13) is once used is exemplified by hydrocarbons such as hexane, hydrolyzed with formic acid to give a compound wherein R' 20 benzene, toluene and the like, halogenated hydrocarbons is aminomethyl, and the obtained compound is reacted with formic acid and formaldehyde to give a compound wherein such as chloroform, dichloromethane, dichloroethane and R’ is dimethylaminomethyl. The reaction is preferably car the like, ethers such as tetrahydrofuran, dioxane, diethyl ried out in a solution of formic acid and formaldehyde as a ether, diisopropyl ether and the like, esters such as acetate solvent, but can be carried out in various inert solvents such 25 and the like, ketones such as acetone, methyl ethyl ketone as methanol, ethanol, tetrahydrofuran, dioxane, benzene, and the like, amides such as dimethylformamide, dimethy dimethylformamide and the like. Generally, it is most advan lacetamide and the like, acetonitrile and dimethyl sulfoxide, tageous that the reaction be carried out for 1-24 hours while and a mixed solvent thereof, which can be selected as refluxing under heating. The reaction can be also carried out appropriate according to the reaction. at a lower temperature. 30 The preparation methods of the compounds of the formula Method -12 (II) are shown in the following Method II-1 to Method I-17, A compound of the formula (I) wherein Y is to which the preparation methods are not limited. -NHCONHCO- is synthesized by reacting the amino compound of the formula (1) or an acid addition salt thereof, Method -1 with an isocyanate of the formula 35 A compound of the formula (II) can be synthesized by reacting a thieno23-e-1,4-diazepine-2-thione compound of the formula wherein Z' is as defined above. The reaction proceeds under the same conditions as in (21) Method I-2. Method I-13 A compound of the formula (I) wherein Y is -NHCSNHCO- is synthesized by reacting the amino compound of the formula (I) or an acid addition salt thereof, with an isothiocyanate of the formula 45 wherein each symbol is as defined above, which is synthe sized by the method described in Arzneim-Forsch/Drug wherein Z is as defined above. Res., vol. 28, p. 1153, with an acid hydrazide compound of The reaction proceeds under the same conditions as in the formula Method -2. 50 Method I-14 A compound of the formula (I) wherein Y is HNNHCO-(CHm-CH(R-Y-Z’ (22) -NHCONHSO- is synthesized by reacting the amino compound of the formula (1) or an acid addition salt thereof, wherein each symbol is as defined above. 55 with an isocyanate of the formula The reaction generally proceeds in an inert solvent such as benzene, toluene, xylene, dioxane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol and the like, in the wherein Z is as defined above. presence of an organic acid (e.g. acetic acid, propionic acid The reaction proceeds under the same conditions as in Method -2. and trifluoroacetic acid), an inorganic acid (e.g., hydrochlo Method -15 ric acid and sulfuric acid) or silica gel, at a temperature of A compound of the formula (I) wherein Y is from room temperature to the refluxing temperature of the -NHCSNHSO- is synthesized by reacting the amino solvent used. Method -2 compound of the formula (1) or an acid addition salt thereof, 65 with an isothiocyanate of the formula A compound of the formula (II) can be synthesized by reacting a compound of the formula 5,760,032 28 the like, halogenated hydrocarbons such as chloroform. (23) dichloromethane, dichloroethane and the like, ethers such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether and the like, esters such as acetate and the like, ketones such R19 as acetone, methyl ethyl ketone and the like, amides such as N dimethylformamide, dimethylacetamide and the like, aceto nitrile and dimethyl sulfoxide, and a mixed solvent thereof. N-NH, The compound of the formula (25) can be obtained by the wherein each symbol is as defined above, which is obtained above reactions, and can be converted to the compound of by reacting the compound of the formula (21) with hydra O the formula (II) without separation. In this case, the reaction zine or a hydrate thereof, with a carboxylic acid of the proceeds in the above-mentioned inert solvent, in the pres formula ence of an organic acid (e.g., acetic acid, propionic acid and trifluoroacetic acid), an inorganic acid (e.g. hydrochloric acid and sulfuric acid) or silica gel at a temperature of from 15 room temperature to the refluxing temperature of the solvent wherein each symbol is as defined above, or a reactive used. derivative thereof. and then subjecting the obtained com Method -3 pound of the formula The compound of the formula (II) can be synthesized by (25) reacting the compound of the formula (23) and an ortho ester 20 derivative of the formula

R9 wherein R is alkyl having 1 to 5 carbon atoms and other N symbols are as defined above. 25 The reaction generally proceeds in an inert solvent (e.g. benzene, toluene, xylene, dioxane, tetrahydrofuran, wherein each symbol is as defined above, to ring closure methanol, ethanol and isopropyl alcohol) in the presence of reaction to form a triazole ring. an organic acid (e.g., acetic acid, propionic acid and trifluo The reaction of the compound of the formula (21) and 30 roacetic acid), an inorganic acid (e.g., hydrochloric acid and hydrazine or a hydrate thereof generally proceeds in an inert sulfuric acid) or silica gel at a temperature of from room solvent such as dioxane, tetrahydrofuran, methanol, ethanol, temperature to the refluxing temperature of the solvent used. isopropyl alcohol, butanol and the like at a temperature of Method I-4 from -20° C. to 50° C. A compound of the formula (II) wherein Y is -NHCO In the reaction of the compound of the formula (23) and 35 is synthesized by condensing an amino compound of the the compound of the formula (24), when the carboxylic acid formula derivative of the formula (24) is an acid halide (e.g., acid chloride and acid bromide) or an acid anhydride (e.g., Ar (27) symmetric acid anhydride, mixed anhydride with lower R N alkyl carbonate, and mixed anhydride with alkylphosphoric R19 acid), the reaction is carried out in an inert solvent or without R S N solvent in the presence of an acid scavenger such as an W organic base (e.g., triethylamine, N-methylmorpholine, pyri N dine and dimethylaniline) or an inorganic base (e.g., alkali N 1 hydrogencarbonate, alkali carbonate and alkali hydroxide) 45 as necessary, at a temperature of from under ice-cooling to (CH)-H-NH. under heating. When the reactive derivative of the formula R3 (24) is a lower alkyl ester (e.g. methyl ester and ethyl ester) or a so-called active ester (e.g., 4-nitrophenyl ester, wherein each symbol is as defined above, or an acid addition 4-chlorobenzyl ester, 4-chlorophenyl ester, succinimide 50 salt thereof and a carboxylic acid of the formula ester, benzotriazole ester and 4-dimethylsulfoniumphenyl HOOC-Z (28) ester), the reaction is carried out in an inert solvent or without solvent at a temperature of from room temperature wherein Z is as defined above, or a reactive derivative to under heating. When the formula (24) is a free carboxylic thereof. acid, the amidation is carried out in the presence of a 55 The above-mentioned condensation can be carried out condensing agent such as carbodiimide e.g., N.N- according to a known method such as amidation. peptide dicyclohexyl- carbodiimide and 1-ethyl-3-(3- synthesis and the like. When the reactive derivative of dimethylaminopropyl)-carbodiimide), diphenylphosphoryl carboxylic acid is an acid halide (e.g., acid chloride and acid azide, carbonyldiimidazole, 1-benzotriazoryloxytris bromide) or an acid anhydride (e.g., symmetric acid (dimethylamino)phosphonium hexafluorophosphate (Bop anhydride, mixed anhydride with lower alkyl carbonate, and reagent), 2-chloro-N-methylpyridinium iodide mixed anhydride with alkylphosphoric acid), the reaction is tributylamine (Mukaiyama method) in an inert solvent or generally carried out in an inert solvent or without solvent, without solvent preferably at a temperature of from -20° C. preferably in the presence of an acid scavenger such as an to 80° C. These reactions generally end in 24 hours. The organic base (e.g., triethylamine. N-methylmorpholine, pyri inert solvent to be used is exemplified by hydrocarbons such 65 dine and dimethylaniline) or an inorganic base (e.g., alkali as hexane, benzene, toluene and the like, alcohols such as hydrogencarbonate, alkali carbonate and alkalihydroxide) at methanol, ethanol, propanol, isopropyl alcohol, butanol and a temperature of from -20°C. to 80° C. When the reactive 5,760,032 29 30 derivative is a lower alkyl ester (e.g. methyl ester and ethyl ester) or a so-called active ester (e.g., 4-nitrophenyl ester, 4-chlorobenzyl ester, 4-chlorophenyl ester, succinimide wherein Z is as defined above. ester, benzotriazole ester and 4-dimethylsulfoniumphenyl The reaction proceeds under the same conditions as in ester), the reaction is generally carried out in an inert solvent Method I-5, or without solvent at a temperature of from -20° C. to the Method I-7 refluxing temperature of the solvent. Amidation of free A compound of the formula (II) wherein Yis-NHSO carboxylic acid is carried out in the presence of a condensing is synthesized by reacting the amino compound of the agent such as carbodiimide (e.g., N,N- formula (27) or an acid addition salt thereof with a sulfonyl dicyclohexylcarbodiimide and 1-ethyl-3-(3- 10 halide of the formula dimethyl a mino propyl)-car bodiimide , diphenylphosphorylazide, carbonyldiimidazole, Z-SO-X (32) 1-benzotriazolyloxytris(dimethylamino)phosphonium wherein Xishalogen such as chlorine, bromine and the like hexafluorophosphate (Bop reagent), 2-chloro-N- and Z is as defined above, or a sulfonic acid anhydride of methylpyridinium iodide-tributylamine (Mukaiyama 15 the formula method) in an inert solvent or without solvent preferably at a temperature of from -20° C. to 80° C. These reactions (Z-SO),O (33) generally end in 24 hours. The inert solvent to be used in the above-mentioned amidation is exemplified by hydrocarbons wherein Z is as defined above. such as hexane, benzene, toluene and the like, halogenated 20 The amidation is carried out preferably in the presence of hydrocarbons such as chloroform, dichloromethane, dichlo an acid scavenger such as an organic base (e.g., roethane and the like, ethers such as tetrahydrofuran, triethylamine. N-methylmorpholine, pyridine and dioxane, diethyl ether, diisopropyl ether and the like, esters dimethylaniline) or an inorganic base (e.g., alkali such as acetate and the like, ketones such as acetone, methyl hydrogencarbonate, alkali carbonate and alkali hydroxide), ethyl ketone and the like, amides such as 25 without solvent or in an inert solvent, preferably at a dimethylformamide, dimethylacetamide and the like, temperature of from -20° C. to 80° C. These reactions acetonitrile, dimethyl sulfoxide and water, and a mixed generally end in 24 hours. The inert solvent to be used is solvent thereof, which can be selected as appropriate accord exemplified by hydrocarbons such as hexane, benzene, ing to the reaction. toluene and the like, halogenated hydrocarbons such as Method I-5 30 chloroform, dichloromethane, dichloroethane and the like, A compound of the formula (II) wherein Y is ethers such as tetrahydrofuran, dioxane, diethyl ether, diiso -NHCONH- is synthesized by reacting the amino com propyl ether and the like, esters such as acetate and the like, pound of the formula (27) or an acid addition salt thereof ketones such as acetone, methyl ethyl ketone and the like, with an isocyanate of the formula amides such as dimethylformamide, dimethylacetamide and 35 the like, acetonitrile and dimethyl sulfoxide, and a mixed solvent thereof, which can be selected as appropriate accord wherein Z is as defined above, or by reacting an amino ing to the reaction. compound of the formula Method I-8 A compound of the formula (II) wherein Y is HN-Z (30) -NHCOO- is synthesized by reacting the amino com wherein Z is as defined above, with phosgene (e.g., trichlo pound of the formula (27) or an acid addition salt thereof romethyl chloroformate and bis(trichloromethyl)carbonate with a compound of the formula or carbonyldiimidazole, and then reacting the resulting reac tion mixture with the amino compound of the formula (27) Z-OCO-X (34) or an acid addition salt thereof. The reaction is carried out in the presence of an acid wherein X is a halogen such as chlorine, bromine and the scavenger such as an organic base (e.g., triethylamine, like and Z is as defined above, or a compound of the N-methylmorpholine, pyridine and dimethylaniline) or an formula inorganic base (e.g., alkali hydrogencarbonate, alkali car (Z-OCO)O (35) bonate and alkalihydroxide) as necessary, without solvent or 50 in an inert solvent, preferably at a temperature of from -20° wherein Z is as defined above. C. to 80° C. These reactions generally end in 24 hours. The The amidation is carried out preferably in the presence of inert solvent to be used is exemplified by hydrocarbons such an acid scavenger such as an organic base (e.g., as hexane, benzene, toluene and the like, halogenated hydro triethylamine, N-methylmorpholine, pyridine and carbons such as chloroform, dichloromethane, dichloroet 55 dimethylaniline) or an inorganic base (e.g., alkali hane and the like, ethers such as tetrahydrofuran, dioxane, hydrogencarbonate, alkali carbonate and alkali hydroxide), diethyl ether, diisopropyl ether and the like, esters such as without solvent or in an inert solvent, preferably at a acetate and the like, ketones such as acetone, methyl ethyl temperature of from -20° C. to 80° C. These reactions ketone and the like, amides such as dimethylformamide, generally end in 24 hours. The inert solvent to be used is dimethylacetamide and the like, acetonitrile and dimethyl exemplified by hydrocarbons such as hexane, benzene, sulfoxide, and a mixed solvent thereof, which can be toluene and the like, halogenated hydrocarbons such as selected as appropriate according to the reaction. chloroform, dichloromethane, dichloroethane and the like, Method I-6 ethers such as tetrahydrofuran, dioxane, diethyl ether, diiso A compound of the formula (II) wherein Y is propyl ether and the like, esters such as acetate and the like, -NHCSNH- is synthesized by reacting the amino com 65 ketones such as acetone, methyl ethyl ketone and the like, pound of the formula (27) or an acid addition salt thereof amides such as dimethylformamide, dimethylacetamide and with an isothiocyanate of the formula the like, acetonitrile and dimethyl sulfoxide, and a mixed 5,760,032 31 32 solvent thereof, which can be selected as appropriate accord diethyl ether, diisopropyl ether and the like, esters such as ing to the reaction. acetate and the like. ketones such as acetone, methyl ethyl Method II-9 ketone and the like, amides such as dimethylformamide, The amino compound of the formula (27) is easily dimethylacetamide and the like, acetonitrile and dimethyl synthesized, for example. according to the method described sulfoxide, and a mixed solvent thereof, which can be in Japanese Patent Unexamined Publication No. 102698/ selected as appropriate according to the reaction. 1974, by deprotecting an amino group of the compound of Method I-11 the formula A compound of the formula (II) wherein Y is --OCO Ar (36) can be easily synthesized by a known esterification reaction O of the carboxylic acid of the formula (28) or an acid halide R N thereof and the hydroxy compound of the formula (37). R19 When an acid halide of the compound of the formula (28) such as acid chloride, acid bromide and the like is used, the R S N W esterification is carried out in an inert solvent or without 15 solvent, preferably at a temperature of from -20° C. to the N 1 N boiling point of the solvent to be used. When a free car boxylic acid of the formula (28) is used, the esterification is (CH2)-CH-Am carried out in the presence of a condensing agent such as k carbodiimide (e.g., N,N-dicyclohexylcarbodiimide and wherein Am is a protected amino group and other symbols 20 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and are as defined above. carbonyldiimidazole, preferably at a temperature of from The amino-protecting group is that which is commonly -20°C. to 80° C. The esterification can be carried out in an used in organic chemistry, such as tert-butyloxycarbonyl, inert solvent, preferably in the presence of an acid catalyst phthaloyl, (substituted) benzoyl, acetyl, trifluoroacetyl, ben (e.g., hydrogen chloride, sulfuric acid and p-toluenesulfonic zyloxycarbonyl and the like. These protecting groups are 25 acid). The reaction may rapidly proceed by raising the easily eliminated by a method using an acid (e.g., hydrof reaction temperature to the boiling point of the solvent to luoric acid, methanesulfonic acid, trifluoromethanesulfonic evaporate the water produced. The inert solvent of the acid, hydrochloric acid, hydrobromic acid, trifluoroacetic above-mentioned esterification is exemplified by hydrocar acid and formic acid), or a method using a base such as an bons such as hexane, benzene, toluene and the like, halo alkali metal hydroxide (e.g., sodium hydroxide, potassium 30 genated hydrocarbons such as chloroform, dichloromethane, hydroxide and barium hydroxide), hydrazine and a hydrate dichloroethane and the like, ethers such as tetrahydrofuran, thereof, or hydrogenolysis using a metal catalyst (e.g., dioxane, diethyl ether, diisopropyl ether and the like, esters palladium and Raney nickel). such as acetate and the like, ketones such as acetone and the Method I-10 like, dimethylformamide, dimethylacetamide and dimethyl A compound of the formula (II) wherein Y is 35 sulfoxide, and a mixed solvent thereof. which can be -OCONH- is synthesized by reacting a hydroxy com selected as appropriate according to the reaction. pound of the formula Method I-12 The hydroxy compound of the formula (37) is easily (37) synthesized according to a known method such as the 40 method described in Japanese Patent Unexamined Publica tion No. 102698/1974. R19 Method L-13 A compound of the formula (II) wherein Y is -NHCONHCO- is synthesized by reacting the amino N 45 compound of the formula (27) or an acid addition salt N 1 thereof with an isocyanate of the formula (CH)-h- OH R3 wherein each symbol is as defined above. with the isocyan wherein Z” is as defined above. ate of the formula (29), or by reacting the amino compound The reaction proceeds under the same conditions as in of the formula (30) with phosgene e.g., trichloromethyl Method I-5. chloroformate and bis(trichloromethyl)carbonate) or Method I-14 carbonyldiimidazole, and then reacting the resulting reaction A compound of the formula (II) wherein Y is mixture with the hydroxy compound of the formula (37) or 55 -NHCSNHCO- is synthesized by reacting the amino an acid addition salt thereof. compound of the formula (27) or an acid addition salt The reaction is carried out in the presence of an acid thereof with an isothiocyanate of the formula scavenger such as an organic base (e.g., triethylamine, N-methylmorpholine, pyridine and dimethylaniline) or an inorganic base (e.g., alkali hydrogencarbonate, alkali car wherein Z is as defined above. bonate and alkalihydroxide) as necessary, without solvent or The reaction proceeds under the same conditions as in in an inert solvent, preferably at a temperature of from -20° Method I-5. C. to 80° C. These reactions generally end in 24 hours. The Method I-15 inert solvent to be used is exemplified by hydrocarbons such A compound of the formula (II) wherein Y is as hexane, benzene, toluene and the like, halogenated hydro 65 -NHCONHSO- is synthesized by reacting the amino carbons such as chloroform, dichloromethane, dichloroet compound of the formula (27) or an acid addition salt hane and the like, ethers such as tetrahydrofuran, dioxane, thereof with an isocyanate of the formula 5,760,032 33 34 or without solvent at a temperature of from -20° C. to the refluxing temperature of the solvent. Amidation of free wherein Z is as defined above. carboxylic acid is carried out in the presence of a condensing The reaction proceeds under the same conditions as in agent such as carbodiimide e.g., N.N- Method -5. dicyclohexylcarbodiimide and 1-ethyl-3-(3- Method -16 dime thy lami no propyl) car bodiimi del, A compound of the formula (II) wherein Y is diphenylphosphorylazide, carbonyldiimidazole, -NHCSNHSO- is synthesized by reacting the amino 1-benzotriazolyloxytris(dimethylamino)phosphonium compound of the formula (27) or an acid addition salt hexafluorophosphate (Bop reagent) and 2-chloro-N- thereof with an isothiocyanate of the formula O methylpyridinium iodide-tributylamine (Mukaiyama method) in an inert solvent or without solvent, preferably at a temperature of from -20° C. to 80° C. These reactions wherein Z is as defined above. generally end in 24 hours. The inert solvent to be used in the The reaction proceeds under the same conditions as in above-mentioned amidation is exemplified by hydrocarbons Method -5. 15 such as hexane, benzene, toluene and the like, halogenated Method - 17 hydrocarbons such as chloroform, dichloromethane, dichlo A compound of the formula (II) wherein Y is roethane and the like, ethers such as tetrahydrofuran, -NHCOCONH- is synthesized by reacting the amino dioxane, diethyl ether, diisopropyl ether and the like, esters compound of the formula (30) or an acid addition salt such as acetate and the like, ketones such as acetone. methyl thereof with oxalyl chloride in an inert solvent in the ethyl ketone and the like, amides such as presence of an acid scavenger such as an organic base (e.g., dimethylformamide, dimethylacetamide and the like, triethylamine, N-methylmorpholine, pyridine and acetonitrile, dimethyl sulfoxide and water, and a mixed dimethylaniline) or an inorganic base (e.g., alkali solvent thereof, which can be selected as appropriate accord hydrogencarbonate, alkali carbonate and alkalihydroxide) at ing to the reaction. room temperature or under ice-cooling, and then reacting the 25 Of the compounds of the formulas (I) and (II), a com obtained compound with the amino compound of the for pound having a free carboxyl group can be also synthesized mula (27), preferably at a temperature of from -20° C. to by a synthesis with protection of carboxyl as an ester and room temperature. These reactions generally end in 24 deprotection at the final step. The deprotection in this case hours. The inert solvent to be used is exemplified by includes those known in organic chemistry (e.g., hydrolysis hydrocarbons such as hexane, benzene, toluene and the like, 30 using acid or base and catalytic reduction using metallic halogenated hydrocarbons such as chloroform, catalyst). A compound having hydroxy can be also synthe dichloromethane, dichloroethane and the like, ethers such as sized in the same manner as above by a synthesis with tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether protection of hydroxy and deprotection at the final step. The and the like, esters such as acetate and the like. ketones such protecting group includes, for example. (substituted) acetyl. as acetone, methyl ethyl ketone and the like, amides such as 35 (substituted) benzoyl, (substituted) benzyl, (substituted) tert dimethylformamide, dimethylacetamide and the like, aceto butyl, tetrahydropyranyl, trimethylsilyl and tert nitrile and dimethyl sulfoxide, and a mixed solvent thereof, dibutyldimethylsilyl, which may be eliminated with ease by which can be selected as appropriate according to the a known method. reaction. Of the compounds of the formulas (I) and (II), a com Of the compounds of the formula (I) and formula (II) of 40 pound having a free 5-tetrazolyl can be synthesized with the present invention, a compound having an acid amide protection of tetrazole ring with trityl (substituted) benzyl structure of -(CH)nCONCR)(R), -(CH)nCONCR) and the like, and deprotection at the final step, or by (R') or -(CH)nCON(R') (R') is also synthesized by conversion of cyano or cyanoalkyl represented by -(CH2) condensing the corresponding carboxylic acid or a reactive nCN which has been obtained by conversion of a compound derivative thereof and an amino compound of the formula 45 having an amide structure represented by -(CH)nCONH by dehydration, and conversion of such cyano to HNCR) (R) (42) 5-tetrazolyl. This tetrazolylation can be carried out by react wherein R and Rare R and R. R. and R', or R and ing a cyano compound with sodium azide or trimethylsilyl R", respectively, and each symbol is as defined above. azide in an inert solvent such as benzene, toluene, xylene, The above-mentioned amidation can be carried out 50 dimethylform amide, pyridine, chloroform, according to a known method such as amidation, peptide dichloromethane, 1,2-dichloroethane, methanol and ethanol synthesis and the like. When the reactive derivative of at a temperature of from 0° C. to 250° C. carboxylic acid is an acid halide (e.g., acid chloride and acid Of the compounds of the formulas (I) and (II), a com bromide) or an acid anhydride (e.g., symmetric acid pound wherein Z and Z are 2-indole and the 3-position of anhydride, mixed anhydride with lower alkyl carbonate, and 55 the indole ring is substituted by halogen can be also syn mixed anhydride with alkylphosphoric acid), the reaction is thesized by directly subjecting a compound wherein the generally carried out in an inert solvent or without solvent, 3-position of indole ring is hydrogen to halogenation. For preferably in the presence of an acid scavenger such as an example, fluorine gas, transition metal fluoride (e.g., cobalt organic base (e.g., triethylamine, N-methylmorpholine, pyri fluoride, silverfluoride and cesium fluoride) or a fluoridated dine and dimethylaniline) or an inorganic base (e.g., alkali reagent (e.g., 1-fluoro-2,6-dichloropyridine, 1-fluoro-3,5- hydrogencarbonate, alkali carbonate and alkalihydroxide) at dichloropyridine and 1-fluoropyridine) is used for fluorida a temperature of from -20° C. to 80° C. When the reactive tion; chlorine, sulfuryl chloride, phosphorus pentachloride, derivative is a lower alkyl ester (e.g. methyl ester and ethyl copper(II) chloride and the like are used for chlorination; ester) or a so-called active ester (e.g., 4-nitrophenyl ester, and bromine is used for bromination. These halogenation 4-chlorobenzyl ester, 4-chlorophenyl ester, succinimide 65 reactions are carried out in an inert solvent or without ester, benzotriazole ester and 4-dimethylsulfoniumphenyl solvent, preferably at -20° C.-80° C. In general, these ester), the reaction is generally carried out in an inert solvent reactions end in 24 hours. Examples of the inert solvent to 5,760,032 35 36 be used for the above halogenation include hydrocarbons suspended in a buffer for binding assay (50 mM MES such as hexane, benzene, toluene and the like, halogenated containing 130 mM sodium chloride, 4.7 mM potassium hydrocarbons such as chloroform, dichloromethane, dichlo chloride, 5 mM magnesium chloride, 0.02% Bacitracin. roethane and the like, ethers such as tetrahydrofuran, 0.0001% phenylmethanesulfonyl fluoride, pH 6.5) and used dioxane, diethyl ether. diisopropyl ether and the like, esters as a peripheral receptor source. In the case of central tissue. such as acetate and the like, ketones such as acetone, methyl rat cerebral cortex was used for the preparation by suspend ethyl ketone and the like, alcohols such as methanol, ing same in a buffer (pH 6.5) containing 5 mM magnesium ethanol, isopropyl alcohol and the like, and amides such as chloride, 1 mM EGTA (ethylene glycol bis(2- dimethylformamide. dimethylacetamide and the like, aminoethylether)tetraacetic acid). 360 mM sodium chloride, acetonitrile. dimethyl sulfoxide and water, and a mixed 10 15 mM potassium chloride. 20 mM HEPES (N-2- solvent thereof, which can be selected as appropriate accord hydroxyethylpiperazine-N-2-ethanesulfonic acid) and 0.25 ing to the reaction. mg/ml. Bacitracin. For binding assay, 50 ul buffer (for total The compounds of the formulas (I) and (II) thus obtained binding use) and unlabelled CCK-8 sulfate (for non-specific can be converted to their salts by, for example, treating the binding) having a final concentration of 1 M or a test compounds with an inorganic acid such as hydrochloric 15 compound ('T-CCK-8, 63-67 TBq/mmol. 40,000-50,000 acid, sulfuric acid, nitric acid, phosphoric acid and hydro cpm, 50 pul) were added to a membrane suspension (450l. bromic acid; an organic acid such as acetic acid, propionic containing 100 g as protein). The reaction mixture was acid, succinic acid, glycolic acid, lactic acid, malic acid, incubated at 20° C. for 30 minutes and filtered through a tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric glass fiber filter (Whatman G/FB) by suction. Immediately acid, methane sulfonic acid, benzenesulfonic acid, thereafter, the filter was washed three times with ice-cold p-toluenesulfonic acid and pamoic acid; an alkali metal such Tris buffer (2.5 ml) and the radioactivity on the filter was as lithium, sodium, potassium, calcium, magnesium and determined. aluminum; an organic base such as piperidine, pyrrollidine. The effects of the test compound on the CCK receptor piperazine, morpholine, guanidine and dicyclohexylamine; binding were evaluated by the concentration (ICs nM) or an amino acid such as aspartic acid, glutamic acid, lysine 25 necessary for inhibiting the specific binding by 50%, which and arginine by a conventional method. was obtained by calculating the inhibition ratio by the When the compound of the present invention has an following formula: asymmetric center in a molecule, the compound is generally obtained as a racemate. The racemate can be resolved into Binding when compound non-specific optical isomers by a conventional method such as chroma was added bindi tography using a column containing an optically active 30 inhibition = 100 Total binding - non-specific bindi x 100 carrier. Such optical isomer can be also produced by the use of an optically active starting compound. Respective dias The results of the effects of the test compounds on the tereomers can be purified by fractional crystallization using CCK receptor binding are shown in the following an optically active acid or base, or chromatography. The compounds of the formulas (I) and (II) of the present 35 invention show superior CCK and gastrin antagonistic Test compound Pancreas (CCK-A) Brain (CCK-B) activities, particularly a strong selective antagonistic action (Example No.) ICs (M) ConM) on CCK-A receptor, as well as strong and long-lasting 11 7.5 >OOO suppression of the secretion of pancreatic enzyme and 14 3.7 >OOO 19 10.6 >OOO gastric acid. Thus, the compounds of the present invention 26 S.6 >OOO are useful as agents for prophylaxis and treatment of dis 27 4.8 OOO eases of central and peripheral nervous systems, such as 59 3.0 >1000 anxiety, schizophrenia, dementia, pain, sitophobia, emesis 72 3.2 >1000 226 110 >OOO and the like, and digestive diseases such as pancreatitis, 45 252 6.6 >1000 gallbladder disorders, gastric ulcer and enterelicosis, irritable 277 9.6 s)O bowel syndrome. constipation. pancreatic malignant tumor 280 2.7 >1000 and the like. Inasmuch as the compounds of the present 36 2.5 >OOO invention are superior in solubility in water and have 338 7.6 >1000 extremely weak affinity for benzodiazepine receptor, they can make pharmaceutical agents superior in properties such 50 In the following, the test method with respect to CCK-A as bioavailability and safety. Moreover, the compound of the antagonistic action is shown. formula (II) can be used as a synthesis starting material of the compound of the formula (I). Experimental Example 2 The pharmacological activity of the compounds of the Effects on CCK-induced secretion of pancreatic juice in 55 guinea pig under anesthesia present invention is shown in the following. Male guinea pigs weighing about 650 g were anesthetized Experimental Example 1 by subcutaneous administration of urethane (1.6 g/kg), and Binding to CCK receptor a cannula for injection of perfusing solution was inserted Whole pancreas was removed from male Wister rats. Fat into the pyloric part of stomach and a discharge cannula was tissue was removed and the pancreas was homogenized inserted at a position 2 cm distal from Treitz ligament. (Blinkman Polytron PT20) in 10 mM MES buffer (0.02% Duodenum was perfused with physiological saline at a rate Bacitracin, 0.02% soy bean-derived trypsin inhibitor, of 8 ml/15 min, and trypsin secretion in the perfusate was 0.0001% phenylmethanesulfonyl fluoride, pH 6.5). The determined. For the determination. Na-benzoyl-arginine homogenate was passed through a nylon cloth (120 mesh) p-nitroanilide (BAPNA) was used as a synthetic substrate and the filtrate was centrifuged at 40,000xg for 15 minutes. 65 and spectrophotometer was used for the determination. The obtained sediment was homogenized in Tris buffer and Secretion of pancreatic juice was induced by an intravenous centrifuged in the same manner as above. The sediment was administration of CCK-8 (0.1 g/kg), and 60 minutes later, 5,760,032 37 38 CCK-8 was administered again. The inhibition ratio of the additive, a pharmaceutical composition is provided. The test compound which was intravenously administered at 5 above-mentioned additive includes, for example, pharma minutes before the second administration of CCK-8 was ceutically acceptable carriers, excipients, diluents, calculated by the following formula: solubilizers, disintegrants, binders and the like. The phar maceutical composition is prepared by mixing the com %. Inhibition = 1 - (amount of tryspin secreted in 60 minutes as a pound of the formula (I) or (II) and the above-mentioned result of induction by second CCK administrationfamount additive to give tablets, powders, capsules, injections, of secretion induced by first CCK administration) x 100 suppositories, infusions and the like, which can be safely The effects of the test compounds on inhibition of secre administered to patients by an oral or parenteral route. The tion of pancreatic juice induced by CCK receptor in guinea 10 dose is generally about 0.5-1.000 mg by oral administration pig under anesthesia are shown in the following and about 0.1-500 mg by intravenous administration to an adult per day. Test compound Dose Inhibition BEST MODE FOR CARRYING OUT THE INVENTION (Example No.) (g/kg) (%) 5 19 3OO 819 it 5.9 (n = 4) The present invention is described in more detail in the 252 300 82.6 t 2.6 (n = 4) following by illustrative Starting Material Preparation 277 300 85.1 it i2.1 (n = 2) Examples (Production Examples) and Examples, to which 280 3OO 78.1 it 7.6 (n = 4) the present invention is not limited. 20 Production Example 1 Experimental Example 3 4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24) Effects on caerulein-induced pancreatitis in rat models triazolo43-a 14-diazepine (50 g) was stirred at 60° C. for The method described in Pancreas, Vol. 5, p. 284 (1990) 7 hours with 2.5% hydrochloric acid (1 l). Then, sodium is modified and used. Caerulein (20 ug/kg) is subcutane 25 hydrogencarbonate was added to the reaction mixture to ously administered 4 times at one hour intervals to male rats make the solution alkaline. The mixture was extracted with weighing about 200 g. Blood is taken and pancreas is ethyl acetate and the extract was dried over sodium sulfate. removed at 4 hours after the last administration. The amy A solution of p-toluenesulfonic acid (58 g) in methanol was lase activity in blood is determined by the method using added thereto, and the mixture was allowed to stand over maltopentaose as a synthetic substrate. After weighing and 30 night. The reaction mixture was filtered to give crystals and fixing with a 10% aqueous formalin solution, the pancreasis the crystals were washed with ethyl acetate and dried to give subjected to hematoxylin-eosin staining and microscopy 50 g of 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- with an optical microscope. The test compound is adminis ethylthiophen-2-yl) (1,2,4-triazole di-p-toluenesulfonate. tered orally or intravenously at 30 minutes before the first Production Example 2 caerulein administration. Amylase activity and inhibition of pancreatic weight gaining are calculated by the following 35 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno 3.2-f formulas. The tissue is rated 0 when changes are not found, 1.2.4 triazolo 4.3-a 14-diazepine (702 g) was suspended and rated from 1 to 4 depending on the degree of changes in a mixed solvent (4.9 l) of ethanol and water (9:1), and found in the tissue, which rating being used to indicate p-toluenesulfonic acid monohydrate (1165 g) was added. improvement in pancreatic tissue disorders. The mixture was stirred at 80° C. for 1.5 hours. The mixture was concentrated to about 2.5 lby evaporating the solvent Amylase activity inhibition (%) = {1 - (Average amylase activity under reduced pressure. and ethyl acetate (41) was added. of group administered with test compound Average amylase The reaction mixture was filtered to give crystals, and the activity of control group) x 100 crystals were washed with ethyl acetate and ethanol and dried to give 1214 g of 3-aminomethyl-4-(3-(2- Inhibition (%) of pancreas weight = {1 - (Average pancreas 45 weight of group administered with test compound Average chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 pancreas weight of control group)} x 100 triazole di-p-toluenesulfonate. mp. 179°-180° C. (dec.) Experimental Example 4 EXAMPLE 1. Effects on CCK-induced delay in gastric emptying in mice 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen The test compound is orally or intravenously administered 2-yl) 1.2.4 triazole di-p-toluenesulfonate (2.0 g) was dis to male mice weighing about 20 g and at 25 minutes solved in dimethylformamide (20 ml), and benzoyl chloride thereafter, CCK-8 (30 g/kg) is subcutaneously adminis (0.42 ml) and triethylamine (1.5 ml) were added under tered. Five minutes later, 1.5% aqueous methyl cellulose ice-cooling. The mixture was stirred at room temperature for solution (0.1 ml) containing 0.05% phenol red is orally 55 8 hours. A saturated aqueous sodium hydrogencarbonate administered. Fifteen minutes later, the content of the stom solution was added to the reaction mixture, and the mixture ach is recovered and mixed with 10% aqueous trichloroace was extracted with ethyl acetate. The organic layer was tic acid solution for deproteinization. After centrifugation, washed with an aqueous citric acid solution and saturated 1N NaOH is added to the supernatant and recentrifuged. brine, and dried over magnesium sulfate. After the solvent Absorbance (590 nm) of the supernatant is determined by was evaporated, the residue was recrystallized from ethyl spectrophotometer. The ratio of improvement is calculated acetate to give 0.3 g of N-(4-(3-(2-chlorobenzoyl)-5- by the following formula. ethylthiophen-2-yl) 1.2.4 triazol-3-ylmethyl)benzamide. Improvement (%) = 1 - (Average absorbance of group administered m.p. 140°-142° C. with test compound Average absorbance of control group)} x 100 65 EXAMPLE 2 By admixing the compound of the formula (I) or (II) of 3,4-Dichlorobenzoic acid (1.52 g) and thionyl chloride the present invention and a pharmaceutically acceptable (6.0 ml) were added to dichloroethane (15 ml), and the 5,760,032 39 40 mixture was refluxed with stirring for 1 hour. The solvent disclosed in Japanese Patent Unexamined Publication No. was evaporated, and the residue was dissolved in dimeth 279374/1991 and thionyl chloride (6.3 ml) were added to ylformamide (20 ml). 3-Aminomethyl-4-(3-(2- dichloroethane (20 ml), and the mixture was refluxed with chlorobenzoyl)-5-ethylthiophen-2-yl) 1.24triazole di-p- stirring for 1.5 hours. The solvent was evaporated, and the toluenesulfonate (5.0 g) and triethylamine (5.0 ml) were 5 residue was dissolved in dimethylformamide (20 ml). added under ice-cooling. The mixture was stirred at room 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- temperature for 1 hour. A saturated aqueous sodium hydro yl) (1,2,4-triazole di-p-toluenesulfonate (5.0 g) and triethy gencarbonate solution was added to the reaction mixture, lamine (5.0 ml) were added to the mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The and the mixture was stirred at room temperature for 1 hour. organic layer was washed with an aqueous citric acid 10 Then, a saturated aqueous sodium hydrogen-carbonate solu solution and saturated brine, and dried over magnesium tion was added to the reaction mixture, and the mixture was sulfate. The solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed recrystallized from ethyl acetate to give 1.62 g of N-(4-(3- with an aqueous citric acid solution and saturated brine, and (2-chlorobenzoyl)-5-ethylthiophen-2-yl) 1,2,4-triazol-3- dried over magnesium sulfate. The solvent was evaporated, ylmethyl)-3,4-dichlorobenzamide. 15 and the residue was recrystallized from ethyl acetate-hexane mp. 158°-160° C. to give 2.36 g of ethyl 2-(4-(3-(2-chlorobenzoyl)-5- ethylthiophen-2-yl) 1.2.4 triazol-3-ylmethylcarbamoyl) EXAMPLE 3 indole-1-acetate. N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) 1.2.4 mp. 158°-160° C. triazol-3-ylmethyl)naphthalene-2-carboxamide (0.98 g) was obtained in the same manner as in Example 2 using EXAMPLE 9 naphthalene-2-carboxylic acid (1.49 g) and 3-aminomethyl 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) 1,2,4) Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) triazole di-p-toluenesulfonate (5.0 g). 1.2.4 triazol-3-ylmethylcarbamoyl)indole-1-acetate (2.0 g) 25 and a solution of sodium hydroxide (0.39 g) in ethanol were mp. 128°-130° C. added to ethanol (20 ml), and the mixture was stirred at 50° EXAMPLE 4 C. for 20 minutes. The solvent was evaporated, and the residue was dissolved in water. Toluene was added to the N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) 12.4) solution for washing. The aqueous layer was taken out, and triazol-3-ylmethyl)guinoline-3-carboxamide (1.17 g) was 2M hydrochloric acid was added to adjust the solution to pH obtained in the same manner as in Example 2 using 2. The solution was extracted with chloroform. The extract quinoline-3-carboxylic acid (1.54 g) and 3-aminomethyl-4- was dried over magnesium sulfate, and the solvent was (3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) (12.4 triazole evaporated. The residue was recrystallized from ethyl di-p-toluenesulfonate (5.0 g). acetate to give 0.45 g of 2-(4-(3-(2-chlorobenzoyl)-5- m.p. 160°-162° C. 35 ethylthiophen-2-yl) 1.24triazol-3-ylmethylcarbamoyl) indole-1-acetic acid. EXAMPLE 5 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) 12.4 mp. 218-220° C. triazol-3-ylmethyl)indole-2-carboxamide (0.67 g) was EXAMPLE 10 obtained in the same manner as in Example 2 using indole 2-carboxylic acid (1.40 g) and 3-aminomethyl-4-(3-(2- 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen chlorobenzoyl)-5-ethylthiophen-2-yl) 1,2,4-triazole di-p- 2-yl)-5-methyl 12.4 triazole di-p-toluenesulfonate (3.70 g) toluenesulfonate (5.0 g). was dissolved in dichloroethane (20 ml). Benzoyl chloride mp. 234°-235° C. (0.64 ml) and triethylamine (2.8 ml) were added to the solution under ice-cooling, and the mixture was stirred at EXAMPLE 6 45 room temperature overnight. A saturated aqueous sodium N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) 1.2.4) hydrogencarbonate solution was added to the reaction triazol-3-ylmethyl)-1-methylindole-2-carboxamide (0.58 g) mixture, and the mixture was extracted with chloroform. was obtained in the same manner as in Example 2 using The organic layer was washed with saturated brine and dried 1-methylindole-2-carboxylic acid (1.52 g) and over magnesium sulfate. The solvent was evaporated. The 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- SO residue was purified by silica gel column chromatography yl) 1.2.4 triazole di-p-toluenesulfonate (5.0 g). (developing solvent:chloroform-methanol), and recrystal lized from ethyl acetate to give 1.50 g of N-(4-(3-(2- m.p. 200°-202° C. chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) EXAMPLE 7 triazol-3-ylmethyl)benzamide, 55 Benzyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) mp. 160°-161° C. 1,2,4-triazol-3-ylmethylcarbamoyl)-2,3-dihydroindole-1- carboxylate (2.57 g) was obtained in the same manner as in EXAMPLE 11 Example 2 using 1-benzyloxycarbonyl-2,3-dihydroindole 3,4-Dichlorobenzoic acid (1.05 g) and thionyl chloride 2-carboxylic acid (2.60 g) and 3-aminomethyl-4-(3-(2- (0.72 ml) were added to dichloroethane (10 ml), and the chlorobenzoyl)-5-ethylthiophen-2-yl) 1.2.4 triazole di-p- mixture was refluxed for 3 hours. The solvent was toluenesulfonate (5.0 g). evaporated, and the residue was dissolved in dichloroethane mp. 161°-165° C. (20 ml). 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5- ethylthiophen-2-yl)-5-methyl(1,2,4triazole di-p- EXAMPLE 8 65 toluenesulfonate (3.70 g) and triethylamine (2.8 ml) were 1-Ethoxycarbonylmethylindole-2-carboxylic acid (2.15 added under ice-cooling, and the mixture was stirred at room g) synthesized by a known method such as the method temperature for 1 hour. A saturated aqueous sodium hydro 5,760,032 41 42 gencarbonate solution was added to the reaction mixture, chromatography (developing solvent: chloroform and the mixture was extracted with chloroform. The organic methanol), and recrystallized from ethyl acetate to give 0.94 layer was washed with an aqueous citric acid solution and g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- saturated brine, and dried over magnesium sulfate. The methyl(1,2,4-triazol-3-ylmethyl)indole-3-carboxamide. solvent was evaporated, and the residue was recrystallized 5 mp. 140°-145° C. from ethyl acetate to give 0.90 g of N-(4-(3-(2- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.24) EXAMPLE 16 triazol-3-ylmethyl)-3,4-dichlorobenzamide. N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- mp. 151-152° C. methyl 1.2.4 triazol-3-ylmethyl)-1-methylindole-2- 10 carboxamide (0.20 g) was obtained in the same manner as in EXAMPLE 12 Example 15 using 1-methylindole-2-carboxylic acid (0.963 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen g) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- 2-yl)-5-methyl(1,2,4-triazole di-p-toluenesulfonate (3.70 g) ethylthiophen-2-yl)-5-methyl(1,2,4-triazole di-p- was dissolved in dimethylformamide (20 ml). Naphthalene toluenesulfonate (3.70 g). 2-carboxylic acid (0.95 g) and diphenylphosphoryl azide 15 mp. 178°-180° C. (1.29 ml) were added under ice-cooling and dissolved in the solution. A solution of triethylamine (2.24 ml) in dimethyl EXAMPLE 7 formamide was dropwise added, and the mixture was tert-Butyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- allowed to stand overnight at room temperature. Then, a yl)-5-methyl 12,4-triazol-3-ylmethylcarbamoyl)indole-1- 10% aqueous citric acid solution was added to the reaction acetate (0.53 g) was obtained in the same manner as in mixture, and the mixture was extracted with ethyl acetate. Example 15 using 1-tert-butoxycarbonylmethylindole-2- The organic layer was washed with a saturated aqueous carboxylic acid (0.790 g) synthesized by a known method sodium hydrogencarbonate solution and saturated brine, and such as the method disclosed in Japanese Patent Unexam dried over magnesium sulfate. The solvent was evaporated, ined Publication No. 1558771/1993 and 3-aminomethyl-4- and the residue was recrystallized from ethyl acetate to give 25 (3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1,24 0.53 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)- triazole di-p-toluenesulfonate (2.07 g). 5-methyl(1,2,4-triazol-3-ylmethyl) naphthalene-2- mp. 164°-165° C. caboxamide, EXAMPLE 18 mp. 1649-165° C. 30 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen EXAMPLE 13 2-yl)-5-methyl(1,24triazole di-p-toluenesulfonate (7.4 g) N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- was dissolved in dimethylformamide (70 ml). methyl(1,2,4-triazol-3-ylmethyl)guinoline-3-carboxamide 1-Ethoxycarbonylmethylindole-2-carbonyl chloride (3.03 g) (0.63 g) was obtained in the same manner as in Example 12 35 and triethylamine (7.0 ml) were added under ice-cooling, using 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- and the mixture was stirred at room temperature for 8 hours. ethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- A saturated aqueous sodium hydrogencarbonate solution toluenesulfonate (3.70 g) and quinoline-3-carboxylic acid was added to the reaction mixture, and the mixture was (0.95 g). extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and mp. 213-214 C. dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from ethanol to give 4.33 g EXAMPLE 14 of ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- methyl 12.4 triazol-3-ylmethylcarbamoyl)indole-1-acetate. methyl(1.2.4 triazol-3-ylmethyl)indole-2-carboxamide 45 mp. 138-140° C. (3.60 g) was obtained in the same manner as in Example 11 using 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- EXAMPLE 19 ethylthiophen-2-yl)-5-methyl 12,4triazole di-p- Methanol (60 ml) and a 2M aqueous sodium hydroxide toluenesulfonate (7.40 g) and indole-2-carboxylic acid (1.77 solution (7.0 ml) were added to ethyl 2-(4-(3-(2- g). 50 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) mp. 252-254° C. triazol-3-ylmethylcarbamoyl)indole-1-acetate (4.0 g), and the mixture was stirred at 50° C. for 30 minutes and at room EXAMPLE 1.5 temperature for 4 hours. Methanol was evaporated, and Indole-3-carboxylic acid (0.885 g) and thionyl chloride water and ethyl acetate were added. The aqueous layer was (4.0 ml) were added to dichloroethane (10 ml), and the 55 taken out, and citric acid was added to adjust the solution to mixture was refluxed with stirring for 5 hours. The solvent pH 3. The solution was extracted with ethyl acetate. The was evaporated, and the residue was dissolved in dichloro organic layer was washed with saturated brine and dried ethane (20 ml). 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5- over magnesium sulfate. The solvent was evaporated, and ethylthiophen-2-yl)-5-methyl 12,4triazole di-p- the residue was recrystallized from ethyl acetate to give 2.6 toluenesulfonate (3.70 g) and triethylamine (3.5 ml) were g of 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- added under ice-cooling, and the mixture was allowed to methyl 124triazol-3-ylmethylcarbamoyl)indole-1-acetic stand overnight at room temperature. A saturated aqueous acid. sodium hydrogencarbonate solution was added to the reac mp. 208°-210° C. tion mixture, and the mixture was extracted with chloro form. The organic layer was washed with saturated brine, 65 EXAMPLE 20 and dried over magnesium sulfate. The solvent was N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- evaporated, and the residue was purified by silica gel column methyl 12.4)triazol-3-ylmethyl)-2,3-dihydrobenzofuran-7- 5,760,032 43 44 carboxamide (1.42 g) was obtained in the same manner as in evaporated, and the residue was purified by silica gel column Example 11 using 2,3-dihydrobenzofuran-7-carboxylic acid chromatography (developing solvent:chloroform-methanol) (0.902 g) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- and recrystallized from ethanol to give 0.90 g of N-(4-(3- ethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- (2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4) toluenesulfonate (3.70 g). triazol-3-ylmethyl)-N'-(3-chlorophenyl)urea. m.p. 127-129° C. mp. 1638-164° C. EXAMPLE 21 EXAMPLE 25 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- 2-yl)-5-methyl 124triazole di-p-toluenesulfonate (4.0 g) 10 methyl 1,2,4-triazol-3-ylmethyl)-N'-(4-chlorophenyl)urea was dissolved in dimethylformamide (20 ml). Phenylacetyl (0.75 g) was obtained in the same manner as in Example 24 chloride (0.9 ml) and triethylamine (3.2 ml) were added using 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno,3,2- under ice-cooling, and the mixture was stirred at room f 1.2.4) triazolo(4.3-a 1.4 diazepine (3.0 g) and temperature for 1.5 hours. A saturated aqueous sodium 4-chlorophenyl isocyanate (0.56 ml). hydrogencarbonate solution was added to the reaction 15 mixture, and the mixture was extracted with ethyl acetate. mp. 155°-158° C. The organic layer was washed with an aqueous citric acid EXAMPLE 26 solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- recrystallized from ethyl acetate to give 1.56 g of N-(4-(3- 20 methyl(1,2,4-triazol-3-ylmethyl)-N'-(3-methylphenyl)urea (2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) (0.90 g) was obtained in the same manner as in Example 24 triazol-3-ylmethyl)-2-phenylacetamide. using 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno3,2- fl 1.2.4 triazolo 4.3-a 1.4-diazepine (2.25 g) and mp. 153°-155° C. 3-methylphenyl isocyanate (0.40 ml). EXAMPLE 22 25 mp. 148-150° C. 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen 2-yl)-5-methyl(1,24triazole di-p-toluenesulfonate (5.0 g) EXAMPLE 27 was dissolved in dichloroethane (80 ml). Phenyl isocyanate N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- (0.807 ml) and triethylamine (2.8 ml) were added at room 30 methyl 12.4 triazol-3-ylmethyl)-N'-(3-methoxyphenyl) temperature, and the mixture was stirred for 4 hours. Then, urea (1.65 g) was obtained in the same manner as in the reaction mixture was washed with water and dried over Example 24 using 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H magnesium sulfate. The solvent was evaporated, and the thieno3.2-f 1.2.4 triazolo43-a 1.4-diazepine (4.0 g) residue was recrystallized from ethyl acetate to give 2.1 g of and 3-methoxyphenyl isocyanate (0.76 ml). N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 35 1.2.4 triazol-3-ylmethyl)-N'-phenylurea. mp. 139°-142° C. mp. 141-143° C. EXAMPLE 28 N-(4-(3-(2-Chlorobenzoyl)-4,5-dimethylthiophen-2-yl)- EXAMPLE 23 5-methyl(1,2,4-triazol-3-ylmethyl)-N'-(3-methylphenyl) 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen urea (2.2 g) was obtained in the same manner as in Example 2-yl)-5-methyl 124triazole di-p-toluenesulfonate (7.40 g) 24 using 4-(2-chlorophenyl)-23.9-trimethyl-6H-thieno 32 was dissolved in dichloroethane (100 ml). 2-Chlorophenyl f) 1.2.4 triazolo 4,3-a 1,4-diazepine (3.0 g) and isocyanate (1.2 ml) and triethylamine (4.2 ml) were added 3-methylphenyl isocyanate (0.6 ml). under ice-cooling, and the mixture was stirred for 4 hours. Then, the reaction mixture was washed with water and dried 45 mp. 1869-188° C. over magnesium sulfate. The solvent was evaporated, and EXAMPLE 29 the residue was purified by silica gel column chromatogra phy (developing solvent:chloroform -methanol) to give 4.50 N-(4- (3 - (2 - Chloro be n zoy 1) - 4, 5, 6.7- g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- tetrahydrobenzothiophen-2-yl)-5-methyl(1,2,4-triazol-3- methyl(12.4)triazol-3-ylmethyl)-N'-(2-chlorophenyl)urea 50 ylmethyl)-N'-(3-methylphenyl)urea (1.3 g) was obtained in as an oil. the same manner as in Example 24 using 6-(2- chlorophenyl)-11-methyl-2.3.4.5-tetrahydro-8H-benzo(b) NMR (270 MHz. CDCl): 1.26(3H,t.J=7.9 Hz), 2.32(3H, thieno3.2-f 1.2.4 triazolo 4.3-a) (1,4-diazepine (2.0 g) s), 2.82(2H.qJ=7.9 Hz), 4.51(1H.dd.J=3.96 Hz,650 Hz). and 3-methylphenyl isocyanate (0.4 ml). 4.65(1H.dd.J-4.94 Hz, 6.50 Hz), 6.80(1H,s), 6.90(1H,m). 55 7.16(1H,m), 7.23-7.40(6H), 7.55(1Hm), 8.00-8.15(2H) mp. 191°-194° C. EXAMPLE 24 EXAMPLE 30 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno3.2-f 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen 1.24triazolo43-a 14-diazepine (2.25 g) was added to 2-yl) 1.24triazole dip-toluenesulfonate (5.0 g) was dis 6M hydrochloric acid (22.5 ml), and the mixture was stirred solved in dimethylformamide (20 ml). Phenyl isocyanate at 80° C. overnight. Then, 3M sodium hydroxide was added (0.87 ml) and triethylamine (3.0 ml) were added under to the reaction mixture to make the mixture alkaline. The ice-cooling, and the mixture was stirred at room temperature mixture was extracted with chloroform and the extract was for 1 hour. A saturated aqueous sodium hydrogencarbonate dried over magnesium sulfate. 3-Chlorophenyl isocyanate 65 solution was added to the reaction mixture, and the mixture (0.4 ml) was added thereto, and the mixture was stirred at was extracted with ethyl acetate. The organic layer was room temperature for 30 minutes. The solvent was washed with an aqueous citric acid solution and saturated 5,760,032 45 46 brine, and dried over magnesium sulfate. The solvent was from ethyl acetate to give 0.73 g of N-(4-(3-(2- evaporated, and the residue was recrystallized from ethyl chlorobenzoyl)-5-ethylthiophen-2-yl)-5-ethyl 1.2.4 triazol acetate-hexane to give 2.47 g of N-(4-(3-(2-chlorobenzoyl)- 3-ylmethyl)-3,4-dichlorobenzamide. 5-ethylthiophen-2-yl) (1.2.4 triazol-3-ylmethyl)-N'- mp. 136°-138° C. phenylurea. mp. 1949-197° C. EXAMPLE 33 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-ethyl Production Example 3 1.2.4 triazol-3-ylmethyl)indole-2-carboxamide (0.79 g) was obtained in the same manner as in Example 32 using 5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno (2, 10 4-(2-chlorophenyl)-2,9-diethyl-6H-thieno 3.2-f 1.24) 3-e 1,4-diazepine (80 g) was suspended in chloroform (2 triazolo43-a 14-diazepine (1.8 g) and indole-2-carbonyl 1) under ice-cooling. Ethyl oxalyl chloride (30.7 ml) was added, and the mixture was stirred for 1 hour. The reaction chloride (1.35 g), mixture was washed with a saturated aqueous sodium hydro mp. 242-243° C. gencarbonate solution, and dried over magnesium sulfate. 15 The solvent was evaporated, and isopropyl ether was added EXAMPLE 34 to give ared solid (92.2 g). The solid (78.8 g) was dissolved Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- in a mixed solvent of toluene (1.51) and acetic acid (13 ml), ethyl(1.2.4 triazol-3-ylmethylcarbamoyl)indole-1-acetate and the solution was refluxed for 3 hours. The reaction (1.4 g) was obtained in the same manner as in Example 32 mixture was concentrated, and the residue was purified by 20 using 4-(2-chlorophenyl)-2.9-diethyl-6H-thieno3.2-f 1.2, silica gel column chromatography (eluted with 4 triazolo 4.3-a 1,4 diazepine (2.1 g) and chloroform:methanol=50:1). 4-(2-Chlorophenyl)-9- 1-(ethoxycarbonylmethyl)indole-2-carbonyl chloride (1.8 ethoxycarbonyl-2-ethyl-6H-thieno3.2-f 1.24triazolo.4, g). 3-a 14-diazepine (23.3 g) was obtained from a fraction m.p. 132-134° C. containing the objective compound. 25 mp. 138°-140° C. EXAMPLE 35 Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- EXAMPLE 31 ethyl 1.2.4 triazol-3-ylmethylcarbamoyl)indole-1-acetate 30 (1.0 g) and a solution of sodium hydroxide (0.13 g) in 4-(2-Chlorophenyl)-9-ethoxycarbonyl-2-ethyl-6H-thieno ethanol were added to ethanol (20 ml), and the mixture was 3.2-f 1.2.4 triazolo43-a 1.4-diazepine (2.1 g) was stirred at 50° C. for 1 hour. The solvent was evaporated, and added to 5% hydrochloric acid (21 ml), and the mixture was the residue was dissolved in Water. Toluene was added to the stirred at 50° C. for 3 hours. Then, potassium carbonate was added to the reaction mixture to make the mixture alkaline. solution for washing. The aqueous layer was taken out, and 35 2M hydrochloric acid was added to adjust the solution to pH The mixture was extracted with ethyl acetate and the extract 2. The solution was extracted with chloroform, and the was dried over sodium sulfate. p-Toluenesulfonic acid (2.0 extract was dried over magnesium sulfate. The solvent was g) was added thereto to give 5-aminomethyl-4-(3-(2- evaporated, and the residue was recrystallized from ethyl chlorobenzoyl)-5-ethylthiophen-2-yl)-3-ethoxycarbonyl(1, acetate to give 0.34 g of 2-(4-(3-(2-chlorobenzoyl)-5- 2,4-triazole di-p-toluenesulfonate. Ethyl acetate (50 ml), ethylthiophen-2-yl)-5-ethyl(1,2,4-triazol-3- phenyl isocyanate (0.54 ml) and triethylamine (2.1 ml) were ylmethylcarbamoyl)indole-1-acetic acid. added thereto at room temperature, and the mixture was stirred for 30 minutes. Then, a saturated aqueous sodium mp. 201-203° C. hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Production Example 4 The organic layer was washed with an aqueous citric acid 45 5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno2. solution and saturated brine, and dried over magnesium 3-e 14-diazepine (20g) was suspended in chloroform (200 sulfate. The solvent was evaporated, and the residue was ml) at room temperature. Cyclohexanecarboxylic acid chlo recrystallized from diisopropyl ether to give 0.67 g of ethyl ride (10.1 g) was added, and the mixture was stirred for 3 (4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-(3- hours. The reaction mixture was washed with a saturated phenylureidomethyl(1,2,4-triazol-3-yl))carboxylate. SO aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was mp. 123°-125° C. evaporated to give an oil. The oil was dissolved in a mixed EXAMPLE 32 solvent of toluene (200 ml) and acetic acid (5.4 ml), and the 55 mixture was refluxed for 3 hours. The reaction mixture was 4-(2-Chlorophenyl)-2,9-diethyl-6H-thieno(32-f 1.24) washed with a saturated aqueous sodium hydrogencarbonate triazolo43-a 1.4-diazepine (1.8 g) was added to 2.5% solution and saturated brine and dried over magnesium hydrochloric acid (35ml), and the mixture was stirred at 60° sulfate. The solvent was evaporated. The residue was puri C. overnight. Then, sodium hydrogencarbonate was added fied by silica gel column chromatography (eluted with ethyl to the reaction mixture to make the mixture alkaline. Chlo acetate), and isopropyl ether was added to give 15 g of roform (40 ml) and 3,4-dichlorobenzoyl chloride (1.15 g) 4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno(3,2-f were added, and the mixture was stirred at room temperature 12.4 triazolo43-a 14-diazepine. for 2 hours. Then, the organic layer was washed with an aqueous citric acid solution and saturated brine, and dried EXAMPLE 36 over magnesium sulfate. After the solvent was evaporated, 65 4-(2-Chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno3, the residue was purified by silica gel column chromatogra 2-f 1.2.4 triazolo 4.3-a) (14) diazepine (1.85g) was added phy (developing solventiethyl acetate) and recrystallized to 2.5% hydrochloric acid (40 ml), and the mixture was 5,760,032 47 48 stirred at 60° C. overnight. Then, sodium hydrogencarbonate 1) at room temperature, and triethylamine (193 ml) was was added to the reaction mixture to make the mixture added. Trifluoroacetic anhydride (70 ml) was dropwise alkaline. The mixture was extracted with ethyl acetate, and added, and the mixture was stirred for 3 hours. The reaction the extract was dried over sodium sulfate. p-Toluenesulfonic mixture was washed with a saturated aqueous sodium hydro acid (2.0 g) was added thereto to give 3-aminomethyl-4-(3- gencarbonate solution, an aqueous citric acid solution and (2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-cyclohexyl 1.2. saturated brine, and dried over magnesium sulfate. The 4triazole di-p-toluenesulfonate. Dimethylformamide (10 solvent was evaporated to give an oil. The oil was dissolved ml),3,4-dichlorobenzoyl chloride (1.16 g) and triethylamine in a mixed solvent of toluene (21) and acetic acid (18.5 ml). (5 ml) were added thereto under ice-cooling, and the mixture and the mixture was refluxed for 3 hours. The reaction was stirred for 2 hours. Then, a saturated aqueous sodium 10 mixture was washed with a saturated aqueous sodium hydro hydrogencarbonate solution was added to the reaction gencarbonate solution and saturated brine, and dried over mixture, and the mixture was extracted with ethyl acetate. magnesium sulfate. The solvent was evaporated. The residue The organic layer was washed with an aqueous citric acid was purified by silica gel column chromatography (eluted solution and saturated brine, and dried over magnesium with a mixed solvent of ethyl acetate and hexane) and sulfate. The solvent was evaporated, and the residue was 5 crystallized from a mixed solvent of ethyl acetate and purified by silica gel column chromatography (developing hexane to give 9.4 g of 4-(2-chlorophenyl)-2-ethyl-9- solvent:ethylacetate) and recrystallized from ethyl acetate to trifluoromethyl-6H-thieno3.2-f 1,2,4-triazolo43-a 1.4 give 0.17 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen diazepine. 2-yl)-5-cyclohexyl ( 1.2.4 triazol-3-ylmethyl)-3,4- dichlorobenzamide. 20 EXAMPLE 40 mp. 206-208 C. 4-(2-Chlorophenyl)-2-ethyl-9-trifluoromethyl-6H-thieno (3.2-f 124triazolo?43-a 1.4)diazepine (1.0 g) was EXAMPLE 37 added to 10% hydrochloric acid (20 ml), and the mixture N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- was stirred at 70° C. overnight. Then, sodium hydrogencar cyclohexyl 124triazol-3-ylmethyl)indole-2-carboxamide 25 bonate was added to the reaction mixture to make the (1.26 g) was obtained in the same manner as in Example 36 mixture alkaline. Chloroform (20 ml) and 3,4- using 4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno dichlorobenzoyl chloride (0.58 g) were added, and the 3.2-fl 1.2.4 triazolo43-a 1.4-diazepine (2.0 g) and mixture was stirred under ice-cooling for 1 hour. Then, the indole-2-carbonyl chloride (1.1 g). organic layer was washed with an aqueous citric acid mp. 196° C. (dec.) 30 solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium EXAMPLE 38 sulfate. The solvent was evaporated, and the residue was Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- recrystallized from ethyl acetate-hexane to give 0.60 g of cyclohexyl 1.2.4 triazol-3-ylmethylcarbamoyl)indole-1- N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- acetate (1.46 g) was obtained in the same manner as in 35 trifluoromethyl 1.2, 4) triazol-3-yl methyl)-3,4- Example 32 using 4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl dichlorobenzamide. 6H-thieno3.2-f 1,2,4-triazolo.4.3-a 1.4-diazepine (2.0 mp. 75-80° C. g) and 1-(ethoxycarbonylmethyl)indole-2-carbonyl chloride (1.6 g). EXAMPLE 41 NMR (270 MHz, DMSO-d): 0.96(3H,t,J-73 Hz), 1.17 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- (3H,t.J=7.3 Hz), 1.1.0-1.90(11H,m), 2.66(2H.qJ=7.3 Hz). trifluoromethyl(1,2,4-triazol-3-ylmethyl)indole-2- 4.19(2H.qJ-7.3 Hz). 4.55(1H.dd.J=15.5 Hz.4.6 Hz), 4.61 carboxamide (0.35 g) was obtained in the same manner as in (1H.dd.J=15.5 Hz.6.6 Hz), 5.23(2H.s), 6.71 (1H,s), Example 40 using 4-(2-chlorophenyl)-2-ethyl-9- 7.12-7.30(5H.m), 7.52-7.65(4H,m), 8.92(1H.dd.J=4.6 45 trifluoromethyl-6H-thieno3.2-f 1.2.4 triazolo 4.3-a 1.4) Hz.6.6 Hz) diazepine (1.0 g) and indole-2-carbonyl chloride (0.62 g). EXAMPLE 39 m.p. 115°-120° C. Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- EXAMPLE 42 cyclohexyl, 1,2,4-triazol-3-ylmethylcarbamoyl)indole-1- acetate (0.8 g) and a solution of sodium hydroxide (0.08 g) Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- in ethanol was added to ethanol (10 ml), and the mixture was trifluoromethyl 1.2.4 triazol-3-ylmethylcarbamoyl)indole stirred at 50° C. for 30 minutes. The solvent was evaporated, 1-acetate (2.0 g) was obtained in the same manner as in and the residue was dissolved in water. Toluene was added Example 40 using 4-(2-chlorophenyl)-2-ethyl-9- to the solution for washing. The aqueous layer was taken 55 trifluoromethyl-6H-thieno 3.2-f 1,2,4-triazolo 4.3-a out, and 2M hydrochloric acid was added to adjust the 1,4-diazepine (2.4 g) and 1-ethoxycarbonylmethylindole solution to pH 2. The solution was extracted with chloro 2-carbonyl chloride (2.1 g). form and the extract was dried over magnesium sulfate. The mp. 193°-196° C. solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 0.36 g of 2-(4-(3-(2- EXAMPLE 43 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-cyclohexyl 12.4 Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- triazol-3-ylmethylcarbamoyl)indole-1-acetic acid. trifluoromethyl(1.24-triazol-3-ylmethylcarbamoyl)indole mp. 159°-162° C. 1-acetate (1.5 g) and a 2M aqueous sodium hydroxide solution (1.25 ml) were added to methanol (20 ml), and the Production Example 5 65 mixture was stirred at room temperature for 30 minutes. 5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno2, Then, the solvent was evaporated and the residue was 3-e) 14-diazepine (100 g) was suspended in chloroform (2 dissolved in water. Ethyl acetate was added to the solution 5,760,032 49 SO for washing. The aqueous layer was taken out, and citric acid the residue was purified by silica gel column chromatogra was added to adjust the solution to pH 3. The solution was phy (developing solventiethyl acetate-methanol) and recrys extracted with ethyl acetate and the extract was dried over tallized from ethyl acetate-hexane to give 1.08 g of ethyl magnesium sulfate. The solvent was evaporated, and the 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-(3,4- residue was crystallized from ethyl acetate to give 2-(4-(3- dichlorobenzoylaminomethyl) 1.2.4 triazol-5-yl) (2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-trifluoromethyl propionate. 1.2.4 triazol-3-ylmethylcarbamoyl)indole-1-acetic acid. mp. 1539-155° C. mp. 2009-203° C. EXAMPLE 46 EXAMPLE 44 10 Ethyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- 4-(2-Chlorophenyl)-9-ethoxycarbonyl-2-ethyl-6H-thieno (3.4-dichlorobenzoylaminomethyl) 1.2.4 triazol-5-yl) 3.2-f 1.2.4 triazolo4.3-a 1.4-diazepine (2.8 g) was propionate (0.7 g) and a 2M aqueous sodium hydroxide added to 5% hydrochloric acid (28 ml), and the mixture was solution (1.13 ml) were added to methanol (10 ml), and the stirred at 50° C. for 3 hours. Then, potassium carbonate was mixture was stirred at 50° C. for 3 hours. The solvent was added to the reaction mixture to make the mixture alkaline. 15 evaporated, and the residue was dissolved in water. Ethyl The mixture was extracted with ethyl acetate and the extract acetate was added to the solution for washing. The aqueous was dried over magnesium sulfate. p-Toluenesulfonic acid layer was taken out, and citric acid was added to adjust the (2.65 g) was added thereto to give 5-aminomethyl-4-(3-(2- solution to pH 3. The solution was extracted with ethyl chlorobenzoyl)-5-ethylthiophen-2-yl)-3-ethoxycarbonyl(1, acetate. The extract was washed with saturated brine and 2,4-triazole di-p-toluenesulfonate. The solvent was evapo dried over magnesium sulfate. The solvent was evaporated, rated without isolation and dichloroethane (50 ml), indole and the residue was recrystallized from diisopropyl ether to 2-carbonyl chloride (1.26 g) and triethylamine (7 ml) were give 0.56 g of 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- added at room temperature. The mixture was allowed to yl)-3-(3,4-dichlorobenzoylaminomethyl) 1,2,4-triazol-5-yl) stand overnight. Then, a saturated aqueous sodium hydro 25 propionic acid. gencarbonate solution was added, and the mixture was mp. 1979-199° C. extracted with dichloroethane. The organic layer was washed with an aqueous citric acid solution and then satu EXAMPLE 47 rated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel 4-(2-Chlorophenyl)-9-(2-ethoxycarbonylethyl)-2-ethyl column chromatography (developing solventiethyl acetate 6H-thieno3.2-f 1.2.4 triazolo(43-a) (14)diazepine (5.78 hexane) and recrystallized from ethanol to give 0.82 g of g) was heated with 5% hydrochloric acid for 3 hours, and the ethyl (4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- mixture was cooled to room temperature. Sodium hydro (indole-2-carbonylaminomethyl) 1.2.4 triazol-3-yl) gencarbonate (25.2 g) and chloroform were added. Indole carboxylate. 2-carbonyl chloride (2.67 g) was added with vigorous 35 stirring, and the mixture was stirred for 4 hours. The organic mp. 233°-235° C. layer was concentrated, and the residue was dissolved in Production Example 6 methanol (39 ml). The solution was hydrolyzed with 2M sodium hydroxide (3.9 ml) and the reaction mixture was 5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno2. made acidic. The mixture was extracted with ethyl acetate 3-e 1.4-diazepine (40 g) was suspended in chloroform (500 and the extract was dried over magnesium sulfate. The ml) under ice-cooling. Ethyl succinyl chloride (19.3 ml) was solvent was evaporated and the obtained residue was recrys added, and the mixture was stirred for 3 hours. The reaction tallized from ethanol to give 0.26 g of 3-(4-(3-(2- mixture was washed with a saturated aqueous sodium hydro chlorobenzoyl)-5-ethylthiophen-2-yl)-3-(indole-2- gencarbonate solution and dried over magnesium sulfate. carbonylaminomethyl) 1.2.4 triazol-5-yl)propionic acid. and the solvent was evaporated to give an oil. The oil was 45 dissolved in a mixed solvent of toluene (1 l) and acetic acid m.p. 155°-165° C. (dec.) (9 ml), and the solution was refluxed for 3 hours. The EXAMPLE 48 reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluted with a 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen mixed solvent of ethyl acetate and methanol). 4-(2- 50 2-yl) 124triazole di-p-toluenesulfonate (5.0 g) was dis Chlorophenyl)-9-(2-ethoxycarbonylethyl)-2-ethyl-6H solved in dimethylformamide (20 ml). thieno3.2-f 1.2.4 triazolo4.3-a 1,4-diazepine (30.0 g) 2-Naphthalenesulfonyl chloride (1.8 g) and triethylamine was obtained as an oil from a fraction containing the (5.0 ml) were added under ice-cooling, and the mixture was objective compound. stirred at room temperature for 5 hours. A saturated aqueous 55 sodium hydrogencarbonate solution was added to the reac EXAMPLE 45 tion mixture, and the mixture was extracted with ethyl 4-(2-Chlorophenyl)-9-(2-ethoxycarbonylethyl)-2-ethyl acetate. The organic layer was washed with an aqueous citric 6H-thieno3.2-f 1.2.4 triazolo4.3-a 14-diazepine (3.3 acid solution and then saturated brine, and dried over g) was added to 5% hydrochloric acid (35 ml), and the magnesium sulfate. The solvent was evaporated, and the mixture was stirred at 40° C. for 4 hours. Then, sodium residue was recrystallized from ethyl acetate to give 2.73 g hydrogencarbonate was added to the reaction mixture to of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) 12.4 make the mixture alkaline. Chloroform (50 ml) and 3,4- triazol-3-ylmethyl)naphthalene-2-sulfonamide. dichlorobenzoyl chloride (1.61 g) were added under ice mp. 165°-167 C. cooling, and the mixture was allowed to stand overnight. EXAMPLE 49 Then, the organic layer was taken out, washed with an 65 aqueous citric acid solution and saturated brine, and dried 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen over magnesium sulfate. The solvent was evaporated, and 2-yl)-5-methyl 12.4 triazole di-p-toluenesulfonate (1.85 g) 5,760,032 51 52 was dissolved in dimethylformamide (20 ml). g) was obtained in the same manner as in Example 50 using 2-Naphthalenesulfonyl chloride (0.62 g) and triethylamine 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- (1.75 ml) were added under ice-cooling, and the mixture was hydroxymethyl-5-methyl(1,2,4-triazole (1.8 g) and allowed to stand overnight. A saturated aqueous sodium 2-methylphenyl isocyanate (0.77 g). hydrogencarbonate solution was added to the reaction 5 mp. 158°-160° C. mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and EXAMPLE 54 dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give (4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 0.32 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)- O 1,2,4-triazol-3-ylmethyl)-3-methylphenyl carbamate (1.28 5-methyl 1.2.4 triazol-3-ylmethyl) naphthalene-2- g) was obtained in the same manner as in Example 50 using Sulfonamide. 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- hydroxymethyl-5-methyl 12.4) triazole (1.8 g) and mp. 184°-186° C. 3-methylphenyl isocyanate (0.73 g). Production Example 7 15 mp. 1749-177° C. 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno3.2-f EXAMPLE 55 124triazolo.43-a 1.4)diazepine (34.3 g) was added to water (500 ml), and conc. sulfuric acid (74 ml) was dropwise (4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl added with vigorous stirring. The mixture was further stirred 1.2.4 triazol-3-ylmethyl)phenyl carbamate (1.89 g) was at 90° C. for 1 hour, and sodium nitrite (74 g) was added. obtained in the same manner as in Example 50 using Then, potassium carbonate was added to the reaction mix 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- ture to make the mixture alkaline. The mixture was extracted hydroxymethyl-5-methyl(1,2,4-triazole (1.8 g) and phenyl with ethyl acetate and washed with water. The mixture was isocyanate (0.65 g). dried over magnesium sulfate. The solvent was evaporated, mp. 184°-186° C. and the residue was recrystallized from ethyl acetate 25 diisopropyl ether to give 26.06 g of 4-(3-(2-chlorobenzoyl) EXAMPLE 56 -5-ethylthiophen-2-yl)-3-hydroxymethyl-5-methyl(1.24) (4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl triazole. 1.24triazol-3-ylmethyl)-3-methoxyphenyl carbamate mp. 145°-148° C. 30 (1.62 g) was obtained in the same manner as in Example 50 using 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- EXAMPLE 50 hydroxymethyl-5-methyl 12,4triazole (1.8 g) and 4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-3- 3-methoxyphenyl isocyanate (0.82 g). hydroxymethyl-5-methyl(1.2.4 triazole (1.8 g) was dis mp. 136°-139° C. solved in tetrahydrofuran (20 ml). 2-Chlorophenyl isocyan 35 ate (0.84 g) was added, and the mixture was stirred at room EXAMPLE 57 temperature for 4 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography 4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-3- (developing solventiethyl acetate-methanol) and recrystal hydroxymethyl-5-methyl(1,24triazole (1.08 g) was dis lized from ethyl acetate-diisopropyl ether to give 1.85g of solved in chloroform (50 ml). Triethylamine (0.34 g) and (4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1. 3,4-dichlorobenzoyl chloride (0.69 g) were added, and the mixture was stirred at room temperature for 2 hours. Then, 2.4 triazol-3-ylmethyl)-2-chlorophenyl carbamate. water was added to the solution for washing, and the mixture mp. 134°-136° C. was dried over magnesium sulfate. The solvent was 45 evaporated, and the residue was purified by silica gel column EXAMPLE 51 chromatography (developing solvent:ethyl acetate (4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl methanol) and recrystallized from ethyl acetate-diisopropyl 12,4-triazol-3-ylmethyl)-3-chlorophenyl carbamate (1.80 ether to give 1.10 g of (4-(3-(2-chlorobenzoyl)-5- g) was obtained in the same manner as in Example 50 using ethylthiophen-2-yl)-5-methyl(1,2,4-triazol-3-ylmethyl)-3,4- 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- dichlorobenzoate. hydroxymethyl-5-methyl 12,4triazole (1.8 g) and m.p. 117-119° C. 3-chlorophenyl isocyanate (0.84 g). m.p. 141-143° C. EXAMPLE 58 (4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl EXAMPLE 52 55 1.24triazol-3-ylmethyl)indole-2-carboxylate (0.35 g) was (4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl obtained in the same manner as in Example 57 using 1,2,4-triazol-3-ylmethyl)-4-chlorophenyl carbamate (1.80 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- g) was obtained in the same manner as in Example 50 using hydroxymethyl-5-methyl(1,24triazole (1.8 g) and indole 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- 2-carbonyl chloride (0.66 g). hydroxymethyl-5-methyl(1,2,4-triazole (1.8 g) and mp. 80°-85° C. 4-chlorophenyl isocyanate (0.84 g). mp. 1699-171° C. Production Example 8 EXAMPLE 53 5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno2, 65 3-e 14-diazepine (200 g) synthesized by the method (4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl described in Artneim-Forsch/Drug Res. 28 (II), Heft 7. 1.2.4 triazol-3-ylmethyl)-2-methylphenyl carbamate (1.66 1153-1158 (1978) was dissolved in chloroform (2.95 l). 5,760,032 53 54 Acid chloride (154.7 g) of N-phthaloylglycine was added at gencarbonate solution and saturated brine, and dried over room temperature, and the mixture was stirred for 2 hours. magnesium sulfate. The solvent was evaporated, and the The reaction mixture was washed with a saturated aqueous residue was crystallized from ethanol and isopropyl ether to sodium hydrogencarbonate solution, and dried over magne give 2.78 g of crude crystals. The crystals were recrystal sium sulfate. The solvent was evaporated. The obtained oil lized from ethanol to give 1.77 g of ethyl 2-(4-(2- was dissolved in a mixed solvent of toluene (4) and acetic chlorophenyl)-2-ethyl-6H-thieno 32-f 1.2.4 triazolo 4.3- acid (68.8 ml), and the solution was refluxed for 3 hours. The a 14-diazepin-9-ylmethylcarbamoyl)indole-1-acetate. reaction mixture was concentrated, and extracted with chlo mp. 215°-217° C. roform. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated l EXAMPLE 62 brine, and dried over magnesium sulfate. The solvent was Crude crystals (1.41 g) of the objective compound were evaporated under reduced pressure. The obtained residue obtained in the same manner as in Example 6 using was crystallized from ethyl acetate to give 185 g of 4-(2- cinnamic acid (0.81 g), 9-aminomethyl-4-(2-chlorophenyl) chlorophenyl)-2-ethyl-9-(N-phthalimidemethyl)-6H-thieno -2-ethyl-6H-thieno (3.2-fl 1.2.4 triazolo4.3-a) (14) (3.2-f 1.2.4 triazolo4.3-a 14)diazepine. Thus obtained 15 diazepine (1.36 g), triethylamine (1.4 ml) and 4-(2-chlorophenyl)-2-ethyl-9-(N-phthalimidemethyl)-6H 1-benzotriazolyloxytris(dimethylamino)phosphonium thieno3.2-f 1.2.4 triazolo43-a 14-diazepine was dis hexafluorophosphate (Bop reagent, 2.43 g). The crystals solved in ethanol (3.71), and hydrazine monohydrate (18.4 were recrystallized from ethanol to give 0.90 g of trans-N- ml) was added, and the mixture was refluxed for 6 hours. (4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo The reaction mixture was concentrated and the residue was 43-a 14-diazepin-9-ylmethyl)-3-phenylacrylamide. dissolved in chloroform. The insoluble matter was filtered mp. 143°-145° C. off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, and crystal EXAMPLE 63 lized from ethanol to give 76.7 g of 9-aminomethyl-4-(2- Ethyl 2-(4-(2-chlorophenyl)-2-ethyl-6H-thieno 3.2-f chlorophenyl)-2-ethyl-6H-thieno3.2-f 12.4)triazolo,43 25 1.24triazolo43-a 14-diazepin-9-ylmethylcarbamoyl) a 1.4-diazepine. indole-1-acetate (0.83 g) obtained in Example 61 was dis solved in methanol (20 ml). A 2M aqueous sodium hydrox EXAMPLE 59 ide solution (1.5 ml) was added, and the mixture was 9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno3, allowed to stand at room temperature for 4 hours. The 2-f 1.24triazolo43-a 14-diazepine (0.28 g) and tri 30 reaction mixture was concentrated, and the residue was ethylamine (0.115 ml) were dissolved in dichloroethane (15 extracted with water. The aqueous layer was washed with ml). 3,4-Dichlorobenzoyl chloride (0.17 g) was added at ethyl acetate. Citric acid was added to adjust the aqueous room temperature, and the mixture was stirred for 1 hour. layer to about pH 3.0, and the layer was extracted with ethyl The reaction mixture was concentrated, and the residue was acetate. The organic layer was washed with saturated brine purified by silica gel column chromatography using a mixed 35 and dried over magnesium sulfate. The solvent was solvent of ethyl acetate and methanol as a developing evaporated, and the residue was crystallized from isopropyl solvent. The obtained solid was recrystallized from a mixed ether to give 0.71 g of crude crystals. The crystals were solvent of ethyl acetate and hexane to give 0.27 g of recrystallized from ethyl acetate to give 0.63 g of 2-(4-(2- N-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3,2-fl 1.2.4 chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24triazolo[4,3- triazolo 4,3-a 1,4 diazepin-9-ylmethyl)-3,4- a 1.4)diazepin-9-ylmethylcarbamoyl)indole-1-acetic acid. dichlorobenzamide. mp. 222-223° C. m.p. 141°-145° C. EXAMPLE 64 EXAMPLE 60 9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno3, 45 2-f 1.24triazolo43-a 1.4-diazepine (1.07 g) was dis N-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24) solved in chloroform (50 ml). 3-Methylphenyl isocyanate triazolo 4.3-a 1.4 diazepin-9-ylmethyl)indole-2- (0.44 g) was added at room temperature, and the mixture carboxamide (0.75 g) was obtained in the same manner as in was stirred for 3 hours. The reaction mixture was Example 59 using 9-aminomethyl-4-(2-chlorophenyl)-2- concentrated, and crystallized from ethyl acetate. The crude ethyl-6H-thieno3.2-f 1.2.4 triazolo 4.3-a) (14)diazepine 50 crystals were recrystallized from methanol to give 1.47 g of (1.79 g), indole-2-carbonyl chloride (1.07 g) and triethy N-(4-(2-chlorophenyl)-2-ethyl-6H-thieno,3,2-f 1.2.4 lamine (0.84 ml). triazolo 4,3-a 1.4 diazepin-9-ylmethyl)-N'-(3- mp. 290°-291° C. methylphenyl)urea. mp. 260°-262° C. EXAMPLE 6 55 1-Ethoxycarbonylmethylindole-2-carboxylic acid (1.36 EXAMPLE 65 g) synthesized by a known method such as the method N-(2-Chlorophenyl)-N'-(4-(2-chlorophenyl)-2-ethyl-6H described in Japanese Patent Unexamined Publication No. thieno 3.2-f 1,2,4-triazolo 4,3-a 1.4-diazepin-9- 279374/1991, 9-aminomethyl-4-(2-chlorophenyl)-2-ethyl ylmethyl)urea (1.53 g) was obtained in the same manner as 6H-thieno3.2-f 1,2,4-triazolo 4.3-a 1.4)diazepine (1.79 in Example 64 using 9-aminomethyl-4-(2-chlorophenyl)-2- g) and triethylamine (1.4 ml) were dissolved in dimethyl ethyl-6H-thieno3.2-f 1.2.4 triazolo[4,3-a) 1,4-diazepine formamide (15 ml). 1-Benzotriazolyloxytris (1.07 g) and 2-chlorophenyl isocyanate (0.51 g). (dimethylamino)phosphonium hexafluorophosphate (Bop mp. 210°-212° C. reagent, 2.43 g) was added at room temperature, and the mixture was stirred for one day. The reaction mixture was 65 EXAMPLE 66 partitioned between ethyl acetate and water. The organic N-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24) layer was washed with a saturated aqueous sodium hydro triazolo 4,3-a 1.4 diazepin-9-ylmethyl)-N'-(3- 5,760,032 SS 56 methoxyphenyl)urea (1.52 g) was obtained in the same acid, and the mixture is stirred at 80° C. overnight. Sodium manner as in Example 64 using 9-aminomethyl-4-(2- hydrogencarbonate is added to the reaction mixture to make chlorophenyl)-2-ethyl-6H-thieno3.2-f 1,2,4-triazolo[4,3- the mixture alkaline. Chloroform and 3,4-dichlorobenzoyl a 14-diazepine (1.07 g) and 3-methoxyphenyl isocyanate chloride are added, and the mixture is stirred at room (0.49 g). 5 temperature for 2 hours to give N-(3-bromo-4-(3-(2- mp. 1979-199° C. chlorobenzoyl)-5-ethylthiophen-2-yl) (1,2,4-triazol-5- ylmethyl)-3,4-dichlorobenzamide. EXAMPLE 67 N-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24) EXAMPLE 72 triazolo4.3-a 1.4)diazepin-9-ylmethyl)-N'-phenylurea 10 9-Bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f (1.43 g) was obtained in the same manner as in Example 64 12.4 triazolo[4,3-a) 1.4-diazepine (1.0 g) was added to using 9-aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno 2M sulfuric acid (26.5 ml), and the mixture was stirred at (32-f 1.2.4 triazolo43-a 14-diazepine (1.07 g) and 80° C. overnight. Sodium hydrogencarbonate was added to the reaction mixture to make the mixture alkaline. Chloro phenyl isocyanate (0.39 g). 15 mp. 230°-232° C. form and indole-2-carbonyl chloride were added, and the mixture was stirred at room temperature for 1.5 hours. The EXAMPLE 68 obtained crystals were filtered and washed with ethyl acetate to give 0.196 g of N-(3-bromo-4-(3-(2-chlorobenzoyl)-5- N-(3-Chlorophenyl)-N'-(4-(2-chlorophenyl)-2-ethyl-6H ethylthiophen-2-yl) 1,2,4-triazol-5-ylmethyl)indole-2- thieno 3.2-f 1.2.4 triazolo 4.3-a 1.4) diazepin-9- carboxamide. ylmethyl)urea (1.53 g) was obtained in the same manner as in Example 64 using 9-aminomethyl-4-(2-chlorophenyl)-2- mp. 241-243° C. ethyl-6H-thieno3.2-f 124triazolo43-a) 1.4-diazepine (1.07 g) and 3-chlorophenyl isocyanate (0.51 g). EXAMPLE 73 mp. 224°-226 C. 25 9-Bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 12.4 triazolot43-a 14-diazepine is added to 2M sulfuric EXAMPLE 69 acid, and the mixture is stirred at 80° C. overnight. Sodium hydrogencarbonate is added to the reaction mixture to make N-(4-Chlorophenyl)-N'-(4-(2-chlorophenyl)-2-ethyl-6H the mixture alkaline. Chloroform and thieno3.2-f 1.2.4 triazolo 4.3-a 1.4) diazepin-9- 30 1-ethoxycarbonylmethylindole-2-carbonyl chloride are ylmethyl)urea (1.31 g) was obtained in the same manner as added, and the mixture is stirred at room temperature for 2 in Example 64 using 9-aminomethyl-4-(2-chlorophenyl)-2- hours to give ethyl 2-(3-bromo-4-(3-(2-chlorobenzoyl)-5- ethyl-6H-thieno32-f 1,2,4-triazolo[4,3-a) (14)diazepine ethylthiophen-2-yl) 1.2.4 triazol-5-ylmethylcarbamoyl) (1.07 g) and 4-chlorophenyl isocyanate (0.51 g). indole-1-acetate. mp. 235°-237° C. 35 EXAMPLE 74 EXAMPLE 70 Ethyl 2-(3-bromo-4-(3-(2-chlorobenzoyl)-5- N-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24) ethylthiophen-2-yl) 1.2.4 triazol-5-ylmethylcarbamoyl) triazolo 4.3-a) (1,4)diazepin-9-ylmethyl)-N'-(2- indole-1-acetate and a 2M aqueous sodium hydroxide solu methylphenyl)urea (1.09 g) was obtained in the same man tion are added to ethanol, and the mixture is refluxed with ner as in Example 64 using 9-aminomethyl-4-(2- stirring for 1 hour. An aqueous citric acid solution is added chlorophenyl)-2-ethyl-6H-thieno 3.2-f 1.2.4 triazolo 4.3- to adjust the reaction mixture to pH 3 to give 2-(3-bromo a) (14)diazepine (1.07 g) and 2-methylphenyl isocyanate 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) 1,2,4-triazol (0.44 g). 5-ylmethylcarbamoyl)indole-1-acetic acid. mp. 185°-187° C. 45 EXAMPLE 75 Production Example 9 9-Bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno,3,2-f 4-(2-Chlorophenyl)-2-ethyl-6H-thieno3,2-f 1.2.4) 1.2.4 triazolo?43-a 14-diazepine is added to 2M sulfuric triazolo.43-a (1,4)diazepine (10g) was dissolved in dichlo 50 acid, and the mixture is stirred at 80° C. overnight. Sodium roethane (100 ml), and bromine (1.7 ml) was added under hydrogencarbonate is added to the reaction mixture to make ice-cooling. The mixture was heated to room temperature, the mixture alkaline. The mixture is extracted with chloro and allowed to stand overnight. The solvent was evaporated, form and the extract is dried over magnesium sulfate. and chloroform was added. The mixture was washed with an 3-Methoxyphenyl isocyanate is added thereto, and the mix aqueous sodium thiosulfate solution, a saturated aqueous ture is stirred at room temperature for 2 hours to give sodium hydrogencarbonate solution and brine, and dried 55 N-(3-bromo-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) over magnesium sulfate. The solvent was evaporated, and 124triazol-5-ylmethyl)-N'-(3-methoxyphenyl)urea. the residue was purified by silica gel column chromatogra phy (developing solventiethyl acetate-hexane) and crystal EXAMPLE 76 lized from ethyl acetate to give 3.4 g of 9-bromo-4-(2- Water (20 ml) and dioxane (20 ml) were added to N-(4- chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo43 (2-chlorophenyl)-2-ethyl-6H-thieno 3.2-f 1,2,4-triazolo?4, a 1,4-diazepine. 3-a 14-diazepin-9-ylmethyl)-3,4-dichlorobenzamide (3.0 m.p. 162°-164° C. g), and conc. sulfuric acid (1.2 ml) was dropwise added with vigorous stirring. Then, the mixture was stirred at 80° C. for EXAMPLE 71 1.5 hours. Sodium nitrite (3.9 g) was added, and the mixture 9-Bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f was further stirred for 1 hour. A saturated aqueous sodium 124triazolo43-a 1.4-diazepine is added to 2M sulfuric hydrogencarbonate solution was added to the reaction 5,760,032 57 58 mixture, and the mixture was extracted with ethyl acetate. the same manner as in Example 1 using 2-aminomethyl-3- The organic layer was dried over magnesium sulfate, and the (3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) 1.3 limidazole solvent was evaporated. The residue was purified by silica and indole-2-carbonyl chloride. gel column chromatography (developing solventiethyl acetate) and recrystallized from a mixed solvent of ethyl EXAMPLE 83 acetate-hexane to give 0.9 g of N-(4-(3-(2-chlorobenzoyl)- Ethyl 2-(1-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) 5-ethylthiophen-2-yl)-3-hydroxymethyl 12,4-triazol-5- 1.3 limidazol-2-ylmethylcarbamoyl)indole-1-acetate is ylmethyl)-3,4-dichlorobenzamide. obtained in the same manner as in Example 1 using m.p. 125°-128° C. 2-aminomethyl-3-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- 10 yl) 1.3 limidazole and 1-ethoxycarbonylmethylindole-2- EXAMPLE 77 carbonyl chloride. 9-Hydroxymethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno 3.2-f 1,2,4-triazolo.4.3-a 14-diazepine (0.5 g) which EXAMPLE 84 can be synthesized by a known method (Japanese Patent 15 Ethyl 2-(1-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) Unexamined Publication No. 102698/1974) was stirred with 13 limidazol-2-ylmethylcarbamoyl)indole-1-acetate is sub 5% hydrochloric acid (10 ml) at 60° C. overnight. Then, jected to alkali hydrolysis using a 2M aqueous sodium sodium hydrogencarbonate was added to the reaction mix hydroxide solution to give 2-(1-(3-(2-chlorobenzoyl)-5- ture to make the mixture alkaline. Chloroform and indole ethylthiophen-2-yl) 13imidazol-2-ylmethylcarbamoyl) 2-carbonyl chloride (0.35 g) were added, and the mixture indole-1-acetic acid. was stirred under ice-cooling for 3 hours. The organic layer was washed with saturated brine and dried over magnesium EXAMPLE 85 sulfate. The solvent was evaporated, and the residue was purified by silica gel thin-layer chromatography (developing N-(1-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) 13 solventiethyl acetate) and recrystallized from ethyl acetate imidazol-2-ylmethyl)-N'-(3-methoxyphenyl)urea is hexane to give 0.015 g of N-(4-(3-(2-chlorobenzoyl)-5- 25 obtained in the same manner as in Example 23 using ethylthiophen-2-yl)-3-hydroxymethyl(1,2,4-triazol-5- 2-aminomethyl-3-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- ylmethyl)indole-2-carboxamide. yl) (13 imidazole and 3-methoxyphenyl isocyanate. mp. 174°-176° C. EXAMPLE 86 30 EXAMPLE 78 N-(1-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) 13 Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- imidazol-2-ylmethyl)-N'-(2-chlorophenyl)urea is obtained hydroxymethyl(1.2.4 triazol-5-ylmethylcarbamoyl)indole in the same manner as in Example 23 using 2-aminomethyl 1-acetate (0.32 g) was obtained in the same manner as in 3-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) 1,3 Example 77 using 9-hydroxymethyl-4-(2-chlorophenyl)-2- 35 imidazole and 2-chlorophenyl isocyanate. ethyl-6H-thieno3.2-f 1.2.4 triazolo43-a 14-diazepine and 1-ethoxycarbonylmethylindole-2-carbonyl chloride, EXAMPLE 87 N-(1-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) 1.3 m.p. 92°-96° C. imidazol-2-ylmethyl)-N'-(3-methylphenyl)urea is obtained EXAMPLE 79 in the same manner as in Example 23 using 2-aminomethyl Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3- 3-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) (1.3 hydroxymethyl(1,2,4-triazol-5-ylmethylcarbamoyl)indole imidazole and 3-methylphenyl isocyanate. 1-acetate is subjected to alkali hydrolysis using a 2M EXAMPLE 88 aqueous sodium hydroxide solution to give 2-(4-(3-(2- 45 chlorobenzoyl)-5-ethylthiophen-2-yl)-3-hydroxymethyl(1, 4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f)-1,2,3,4- 24triazol-5-ylmethylcarbamoyl)indole-1-acetic acid. tetrazolo 4.5-a 14-diazepine synthesized by a known method (see Japanese Patent Unexamined Publication No. EXAMPLE 80 26297/1974) is hydrolyzed in the same manner as in Example 89, and reacted with 3,4-dichlorobenzoyl chloride N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-3- SO to give N-(1-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-1. hydroxymethyl (1.2.4 triazol-5-ylmethyl)-N'-(3- 2,3,4-tetrazol-5-ylmethyl)-3,4-dichlorobenzamide. methoxyphenyl)urea is obtained in the same manner as in Example 294 using 9-hydroxymethyl-4-(2-chlorophenyl)-2- EXAMPLE 89 ethyl-6H-thieno 3.2-f 1.2.4 triazolo43-a 14-diazepine, camphor-10-sulfonic acid and 3-methoxyphenyl isocyanate. 55 4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f)-1,2,3,4- tetrazolo 4.5-a) 1,4-diazepine (2.0 g) and p-toluenesulfonic EXAMPLE 81 acid monohydrate (3.5 g) were added to a mixed solvent (20 ml) of ethanol-water (9:1), and the mixture was refluxed N-(1-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) (13) under heating for 2 hours. The solvent was evaporated. imidazol-2-ylmethyl)-3,4-dichlorobenzamide is obtained in Dimethylformamide (20 ml), indole-2-carbonyl chloride the same manner as in Example 1 using 2-aminomethyl-3- (1.4 g) and triethylamine (5.0 ml) were added under ice (3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) (13)imidazole cooling, and the mixture was stirred for 1 hour. The reaction and 3,4-dichlorobenzoyl chloride. mixture was partitioned between ethyl acetate and a satu EXAMPLE 82 rated aqueous sodium hydrogencarbonate solution. The 65 organic layer was washed with brine, an aqueous citric acid N-(1-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl) 1.3) solution and brine. The solvent was concentrated under imidazol-2-ylmethyl)indole-2-carboxamide is obtained in reduced pressure. The obtained residue was purified by silica

5,760,032 69 70 a 14-diazepine-2-carboxylic acid (0.19 g) was obtained in obtained in the same manner as in Example 1 using the same manner as in Example 63 using ethyl 4-(2- 4-bromobenzoyl chloride and 3-aminomethyl-4-(3-(2- chlorophenyl)-9(1H-indol-2-yl)carbonylaminomethyl)-6H chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.24) thieno3.2-f 1.2.4 triazolo43-a 14-diazepine-2- triazole. carboxylate (0.4 g), methanol (5 ml) and a 2N aqueous sodium hydroxide solution (0.8 ml). EXAMPLE 1.78 mp. 279-280° C. N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- EXAMPLE 170 methyl 12.4 triazol-3-ylmethyl)-3-bromobenzamide is obtained in the same manner as in Example 1 using Ethyl 4-(2-chlorophenyl)-9-(3-(3-methylphenyl) 10 3-bromobenzoyl chloride and 3-aminomethyl-4-(3-(2- ureidomethyl)-6H-thieno3.2-f 1.2.4 triazolo[4,3-a 1.4) chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 diazepine-2-carboxylate is subjected to alkali hydrolysis to give 4-(2-chlorophenyl)-9-(3-(3-methylphenyl) triazole. ureidomethyl)-6H-thieno3.2-f 1.2.4 triazolo43-a 1.4) EXAMPLE 179 diazepine-2-carboxylic acid. 15 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- EXAMPLE 171 methyl 12,4-triazol-3-ylmethyl)-4-iodobenzamide is Ethyl 4-(2-chlorophenyl)-9-(3-(2-chlorophenyl) obtained in the same manner as in Example 1 using ureidomethyl)-6H-thieno3.2-f 1.24triazolo43-a) (1.4) 4-iodobenzoyl chloride and 3-aminomethyl-4-(3-(2- diazepine-2-carboxylate is subjected to alkali hydrolysis to 20 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) give 4-(2-chlorophenyl)-9-(3-(2-chlorophenyl) triazole. ureidomethyl)-6H-thieno3.2-f 1.2.4 triazolo[4,3-a 1.4) diazepine-2-carboxylic acid. EXAMPLE 18O N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- EXAMPLE 172 25 methyl(1,2,4-triazol-3-ylmethyl)-3-iodobenzamide is Ethyl 4-(2-chlorophenyl)-9-(3-(3-methoxyphenyl) obtained in the same manner as in Example 1 using ureidomethyl)-6H-thieno3.2-f 1.2.4 triazolo43-a 1.4) 3-iodobenzoyl chloride and 3-aminomethyl-4-(3-(2- diazepine-2-carboxylate is subjected to alkali hydrolysis to chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) give 4-(2-chlorophenyl)-9-(3-(3-methoxyphenyl) triazole. ureidomethyl)-6H-thieno3.2-f 1.2.4 triazolo43-a) (1,4) 30 diazepine-2-carboxylic acid. EXAMPLE 181 EXAMPLE 173 1-(2-Methoxycarbonylethyl)indole-2-carboxylic acid N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- (0.81 g) and thionyl chloride (2.6 ml) were dissolved in methyl(1,2,4-triazol-3-ylmethyl)-3,4-dimethylbenzamide is 35 dichloroethane (10 ml), and the mixture was refluxed for 4 obtained in the same manner as in Example 1 using 3,4- hours. The reaction mixture was concentrated, and the dimethylbenzoyl chloride and 3-aminomethyl-4-(3-(2- residue was dissolved in dimethylformamide (15 ml). chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4) 3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- triazole. yl)-5-methyl(1,24triazole ditosylate (2.22 g) and triethy lamine (2.1 ml) were added at room temperature, and the EXAMPLE 174 mixture was stirred for 3 hours. The reaction mixture was N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- partitioned between ethyl acetate and water. The organic methyl(1,2,4-triazol-3-ylmethyl)-4-chlorobenzamide is layer was washed with an aqueous citric acid solution, a obtained in the same manner as in Example 1 using saturated aqueous sodium hydrogencarbonate solution and 4-chlorobenzoyl chloride and 3-aminomethyl-4-(3-(2- 45 saturated brine, and dried over magnesium sulfate. The chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) solvent was evaporated, and the obtained residue was puri triazole. fied by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as an eluent to give EXAMPLE 175 180 mg of methyl 3-(2-(4-(3-(2-chlorobenzoyl)-5- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- SO ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3- methyl(1,2,4-triazol-3-ylmethyl)-3-chlorobenzamide is ylmethylcarbamoyl)indol-1-yl)propionate. obtained in the same manner as in Example 1 using mp. 67-68° C. 3-chlorobenzoyl chloride and 3-aminomethyl-4-(3-(2- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4 EXAMPLE 182 triazole. 55 Methyl 3-(2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- EXAMPLE 176 yl)-5-methyl 12.4 triazol-3-ylmethylcarbamoyl)indol-1-yl) propionate (100 mg) was subjected to alkali hydrolysis and N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- treated in the same manner as in Example 19 to give 85 mg methyl 1.2.4 triazol-3-ylmethyl)-2-chlorobenzamide is of 3-(2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- obtained in the same manner as in Example 1 using methyl(1,2,4-triazol-3-ylmethylcarbamoyl)indol-1-yl) 2-chlorobenzoyl chloride and 3-aminomethyl-4-(3-(2- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) propionic acid. triazole. mp. 224°-225 C. EXAMPLE 1.83 EXAMPLE 177 65 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- methyl(1,2,4-triazol-3-ylmethyl)-4-bromobenzamide is methyl 1.2,4-triazol-3-ylmethyl)-5-chloroindole-2- 5,760,032 71 72 carboxamide is obtained in the same manner as in Example EXAMPLE 189 1 using 5-chloroindole-2-carbonyl chloride and N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- methyl 12,4triazol-3-ylmethyl)-N'-(2-methylphenyl)urea yl)-5-methyl 1.2.4 triazole. is obtained in the same manner as in Example 22 using 2-methylphenyl isocyanate and 3-aminomethyl-4-(3-(2- EXAMPLE 1.84 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) 5-Fluoroindole-2-carboxylic acid (0.50 g) and triazole. 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- yl)-5-methyl(1,24triazole ditosylate (2.07 g) were dis EXAMPLE 190 solved in dimethylformamide (40 ml). Triethylamine (1.6 O N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- ml) and 1-benzotriazolyloxytris(dimethylamino) methyl(1,2,4-triazol-3-ylmethyl)-N'-(4-methylphenyl)urea phosphonium hexafluorophosphate (Bop reagent, 1.29 g) is obtained in the same manner as in Example 22 using were added under ice-cooling, and the mixture was stirred 4-methylphenyl isocyanate and 3-aminomethyl-4-(3-(2- for 4 hours. The reaction mixture was partitioned between chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1.2.4 water and ethyl acetate. The organic layer was washed with 15 triazole. an aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried EXAMPLE 191 over magnesium sulfate. The solvent was evaporated, and N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- the obtained residue was crystallized from ethyl acetate to methyl(1,2,4-triazol-3-ylmethyl)-N'-(2-methoxyphenyl) give 0.23 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen 20 urea is obtained in the same manner as in Example 22 using 2-yl)-5-methyl 12.4 triazol-3-ylmethyl)-5-fluoroindole-2- 2-methoxyphenyl isocyanate and 3-aminomethyl-4-(3-(2- carboxamide. chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 mp. 248-265 C. (decomposition) triazole. EXAMPLE 1.85 25 EXAMPLE 192 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- methyl 1.2.4 triazol-3-ylmethyl)-N'-(4-methoxyphenyl) methyl 12.4) triazol-3-yl methyl)-5-methoxyindole-2- urea is obtained in the same manner as in Example 22 using carboxamide is obtained in the same manner as in Example 4-methoxyphenyl isocyanate and 3-aminomethyl-4-(3-(2- 1 using 5-methoxyindole-2-carbonyl chloride and 30 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1,2,4) 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- triazole. yl)-5-methyl 124triazole. EXAMPLE 193 EXAMPLE 186 tert-Butyl 3-aminophenylacetate (2.07 g) was dissolved in trans-Cinnamic acid (1.48 g), 3-aminomethyl-4-(3-(2- 35 tetrahydrofuran (70 ml), and N,N-carbonyldiimidazole (1.7 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.24) g) was added under ice-cooling. One hour later, triethy triazole di-p-toluenesulfonate (7.42 g) and triethylamine lamine (2.8 ml) and 3-aminomethyl-4-(3-(2-chlorobenzoyl) (5.6 ml) were dissolved in dimethylformamide (50 ml). -5-ethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- 1-Benzotriazolyloxytris(dimethylamino)phosphonium toluenesulfonate (7.42 g) were added, and the mixture was hexafluorophosphate (Bop reagent, 4.42 g) was added, and stirred at room temperature for one day. The reaction mix the mixture was stirred for one day. The reaction mixture ture was concentrated, and partitioned between ethyl acetate was partitioned between ethyl acetate and water. The organic and water. The organic layer was washed with a 5% aqueous layer was washed with a saturated aqueous sodium hydro citric acid solution, a saturated aqueous sodium hydrogen gencarbonate solution and saturated brine, and dried over carbonate solution and saturated brine, and dried over mag magnesium sulfate. The solvent was evaporated to give 5.05 45 nesium sulfate. The solvent was evaporated, and crude g of crude crystals. The crystals were recrystallized from crystals (2.58 g) were precipitated from a small amount of ethyl acetate to give 3.25 g of trans-N-(4-(3-(2- ethyl acetate. The crystals were recrystallized from ethyl chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4 acetate to give 1.66 g of tert-butyl 3-(3-(4-(3-(2- triazol-3-ylmethyl)-3-phenylacrylamide. chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 mp. 150°-151° C. 50 triazol-3-ylmethyl)ureido)phenylacetate. mp. 1789-179° C. EXAMPLE 1.87 EXAMPLE 194 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- tert-Butyl 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen methyl(1.24)triazol-3-ylmethyl)benzofuran-2-carboxamide 55 2-yl)-5-methyl 1,2,4-triazol-3-ylmethyl)ureido) is obtained in the same manner as in Example 1 using phenylacetate (0.92 g) was dissolved in formic acid (20 ml), benzofuran-2-carbonyl chloride and 3-aminomethyl-4-(3- and the solution was allowed to stand at room temperature (2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1.2.4) for one day. The reaction mixture was concentrated, and the triazole. obtained residue was recrystallized from ethyl acetate and isopropyl ether to give 0.66 g of 3-(3-(4-(3-(2- EXAMPLE 188 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.24) N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- triazol-3-ylmethyl)ureido)phenylacetic acid. methyl 1.2.4 triazol-3-ylmethyl)benzothiophene-2- mp. 162°-164° C. carboxamide is obtained in the same manner as in Example 1 using benzothiophene-2-carbonyl chloride and 65 EXAMPLE 195 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- 3,4-Dichlorobenzene sulfonyl chloride and yl)-5-methyl 12.4 triazole. 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- 5,760,032 73 74 yl)-5-methyl(1,2,4-triazole are reacted, and treated in the EXAMPLE 202 same manner as in Example 48 to give N-(4-(3-(2- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 N-(4-(3-(2-Chlorobenzoyl)-5-methylthiophen-2-yl)-5- triazol-3-ylmethyl)-3,4-dichlorobenzenesulfonamide. methyl(1,2,4-triazol-3-ylmethyl)-N'-(3-methylphenyl)urea 5 is obtained in the same manner as in Example 31 using EXAMPLE 1.96 3-methylphenyl isocyanate and 3-aminomethyl-4-(3-(2- chlorobenzoyl)-5-methylthiophen-2-yl)-5-methyl 12.4 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- methyl 1.2.4 triazol-3-ylmethyl)-N'-phenylthiourea is triazole. obtained in the same manner as in Example 22 using phenyl EXAMPLE 203 isothiocyanate and 3-aminomethyl-4-(3-(2-chlorobenzoyl)- O 5-ethylthiophen-2-yl)-5-methyl 12.4 triazole. N-(4-(3-(2-Chlorobenzoyl)-5-methylthiophen-2-yl)-5- methyl 12.4)triazol-3-ylmethyl)-N'-(3-methoxyphenyl) EXAMPLE 1.97 urea is obtained in the same manner as in Example 31 using N-(4-(3-(2-Chlorobenzoyl)-5-methylthiophen-2-yl)-5- 3-methoxyphenyl isocyanate and 3-aminomethyl-4-(3-(2- methyl 12.4 triazol-3-ylmethyl)-3,4-dichlorobenzamide is S chlorobenzoyl)-5-methylthiophen-2-yl)-5-methyl 12.4) obtained in the same manner as in Example 36 using triazole. 3,4-dichlorobenzoyl chloride and 3-aminomethyl-4-(3-(2- chlorobenzoyl)-5-methylthiophen-2-yl)-5-methyl(12.4) EXAMPLE 2.04 triazole. N-(4-(3-(2-Chlorobenzoyl)thiophen-2-yl)-5-methyl 12, 20 4triazol-3-ylmethyl)-3,4-dichlorobenzamide is obtained in EXAMPLE 198 the same manner as in Example 36 using 3,4- N-(4-(3-(2-Chlorobenzoyl)-5-methylthiophen-2-yl)-5- dichlorobenzoyl chloride and 3-aminomethyl-4-(3-(2- methyl 12.4 triazol-3-ylmethyl)indole-2-carboxamide (115 chlorobenzoyl)thiophen-2-yl)-5-methyl1,2,4-triazole. mg) was obtained in the same manner as in Example 2 using 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-methylthiophen 25 EXAMPLE 2.05 2-yl)-5-methyl(1,2,4-triazole di-p-toluenesulfonate (500 N-(4-(3-(2-Chlorobenzoyl)thiophen-2-yl)-5-methyl-1,2. mg) obtained in the same manner as in Production Example 4triazol-3-ylmethyl)indole-2-carboxamide is obtained in 1 and indole-2-carbonyl chloride (148 mg). the same manner as in Example 36 using indole-2-carbonyl mp. 251°-252° C. 30 chloride and 3-aminomethyl-4-(3-(2-chlorobenzoyl) thiophen-2-yl)-5-methyl 12.4 triazole. EXAMPLE 199 4-(2-Chlorophenyl)-2,9-dimethyl-6H-thieno3.2-f 1.2, EXAMPLE 2.06 4triazolo 4,3-a 1.4-diazepine (4.15 g) was dissolved in Ethyl 2-(4-(3-(2-chlorobenzoyl)thiophen-2-yl)-5-methyl 5% hydrochloric acid (50 ml), and the solution was stirred 35 1.2.4 triazol-3-ylmethylcarbamoyl)indole-1-acetate is at 60° C. for 4 hours. The reaction mixture was cooled in a obtained in the same manner as in Example 36 using water bath, and chloroform (60 ml) and sodium hydrogen 1-ethoxycarbonylmethylindole-2-carbonyl chloride and carbonate (12.6 g) were added with vigorous stirring. Then, 3-aminomethyl-4-(3-(2-chlorobenzoyl)thiophen-2-yl)-5- 1-ethoxycarbonylmethylindole-2-carbonyl chloride (3.52 g) methyl 124triazole. was added, and the mixture was stirred for 1 hour. The chloroform layer was washed with saturated brine and dried EXAMPLE 207 over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatogra Ethyl 2-(4-(3-(2-chlorobenzoyl)thiophen-2-yl)-5-methyl phy using a mixed solvent of ethyl acetate and methanol as 1.24)triazol-3-ylmethylcarbamoyl)indole-1-acetate is sub eluent and crystallized from a mixed solvent of ethyl acetate 45 jected to alkalihydrolysis to give 2-(4-(3-(2-chlorobenzoyl) and hexane to give 6.23 g of ethyl 2-(4-(3-(2- thiophe n-2-yl)-5-methyl ( 1.2.4 triazol-3- chlorobenzoyl)-5-methylthiophen-2-yl)-5-methyl 12.4 ylmethylcarbamoyl)indole-1-acetic acid. triazol-3-ylmethylcarbamoyl)indole-1-acetate. EXAMPLE 208 mp. 153°-154° C. 50 N-(4-(3-(2-Chlorobenzoyl)thiophen-2-yl)-5-methyl 12, EXAMPLE 200 4triazol-3-ylmethyl)-N'-(2-chlorophenyl)urea is obtained in Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-methylthiophen-2-yl)- the same manner as in Example 31 using 2-chlorophenyl 5-methyl 1.2.4 triazol-3-ylmethylcarbamoyl)indole-1- isocyanate and 3-aminomethyl-4-(3-(2-chlorobenzoyl) thiophen-2-yl)-5-methyl 12,4-triazole. acetate (2.0 g) was subjected to alkali hydrolysis in the same 55 manner as in Example 19 to give 1.34 g of 2-(4-(3-(2- chlorobenzoyl)-5-methylthiophen-2-yl)-5-methyl 12.4 EXAMPLE 209 triazol-3-ylmethylcarbamoyl)indole-1-acetic acid. N-(4-(3-(2-Chlorobenzoyl)thiophen-2-yl)-5-methyl(1,2, mp. 1949-196° C. 4triazol-3-ylmethyl)-N'-(3-methylphenyl)urea is obtained in the same manner as in Example 31 using 3-methylphenyl EXAMPLE 2.01 isocyanate and 3-aminomethyl-4-(3-(2-chlorobenzoyl) N-(4-(3-(2-Chlorobenzoyl)-5-methylthiophen-2-yl)-5- thiophen-2-yl)-5-methyl(1,2,4-triazole. methyl 12.4 triazol-3-ylmethyl)-N'-(2-chlorophenyl)urea is obtained in the same manner as in Example 31 using EXAMPLE 210 2-chlorophenyl isocyanate and 3-aminomethyl-4-(3-(2- 65. N-(4-(3-(2-Chlorobenzoyl)thiophen-2-yl)-5-methyl(1,2, chlorobenzoyl)-5-methylthiophen-2-yl)-5-methyl(1.24) 4triazol-3-ylmethyl)-N'-(3-methoxyphenyl)urea is obtained triazole. in the same manner as in Example 31 using 5,760,032 75 76 3-methoxyphenyl isocyanate and 3-aminomethyl-4-(3-(2- the same manner as in Example 36 using 3.4- chlorobenzoyl)thiophen-2-yl)-5-methyl 124triazole. dichlorobenzoyl chloride and 3-aminomethyl-4-(3-benzoyl 5-ethylthiophen-2-yl)-5-methyl 12,4-triazole. EXAMPLE 211 N-(4-(3-(2-Chlorobenzoyl)-4,5-dimethylthiophen-2-yl)- EXAMPLE 2.19 5-methyl 12.4 triazol-3-ylmethyl)-3,4-dichlorobenzamide 2-Ethyl-9-methyl-4-phenyl-6H-thieno?3.2-f 1.2.4) is obtained in the same manner as in Example 36 using triazolo 4.3-a 1.4 diazepine (92.4 mg) and 3,4-dichlorobenzoyl chloride and 3-aminomethyl-4-(3-(2- 10-camphorsulfonic acid (2.1 g) were dissolved in a mixed chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-5-methyl 12.4) solvent (25 ml) of ethanolwater (9:1), and the solution was triazole. 10 refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dis EXAMPLE 212 solved in dimethylformamide (10 ml). Indole-2-carbonyl chloride (538 mg) and triethylamine (1.4 ml) were added, N-(4-(3-(2-Chlorobenzoyl)-4,5-dimethylthiophen-2-yl)- and the mixture was stirred at room temperature for one day. 5-methyl(1,2,4-triazol-3-ylmethyl)indole-2-carboxamide 15 The reaction mixture was partitioned between ethyl acetate (160mg) was obtained in the same manner as in Example 2 and water. The organic layer was washed with a saturated using 3-aminomethyl-4-(3-(2-chlorobenzoyl)-4,5- aqueous sodium hydrogencarbonate solution and saturated dimethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- brine, and dried over magnesium sulfate. The solvent was toluenesulfonate (1.0 g) and indole-2-carbonyl chloride concentrated under reduced pressure, and the obtained solid (0.27 g). 20 was recrystallized from a mixed solvent of ethyl acetate and mp. 273°C. (dec.) methanol to give 0.57 g of N-(4-(3-benzoyl-5- ethylthiophen-2-yl)-5-methyl(1.2.4 triazol-3-ylmethyl) EXAMPLE 2.13 indole-2-carboxamide. m.p. 214°-215° C. Ethyl 2-(4-(3-(2-chlorobenzoyl)-4,5-dimethylthiophen-2- 25 yl)-5-methyl(1,2,4-triazol-3-ylmethylcarbamoyl)indole-1- EXAMPLE 220 acetate is obtained in the same manner as in Example 36 using 1-ethoxycarbonylmethylindole-2-carbonyl chloride 2-Ethyl-9-methyl-4-phenyl-6H-thieno3.2-f 1.2.4 and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-4,5- triazolo 4.3- a 1.4 diazepine (1.07 g) and dimethylthiophen-2-yl)-5-methyl 124triazole. 10-camphorsulfonic acid (2.55 g) were dissolved in a mixed 30 solvent (25 ml) of ethanol:water (9:1), and the solution was EXAMPLE 214 refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dis Ethyl 2-(4-(3-(2-chlorobenzoyl)-4,5-dimethylthiophen-2- solved in dimethylformamide (10 ml). yl)-5-methyl(1,2,4-triazol-3-ylmethylcarbamoyl)indole-1- 1-Ethoxycarbonylmethylindole-2-carbonyl chloride (1.06 g) acetate is subjected to alkali hydrolysis to give 2-(4-(3-(2- 35 and triethylamine (2.55 ml) were added, and the mixture was chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-5-methyl(1.2. stirred at room temperature for one day. The reaction mix 4triazol-3-ylmethylcarbamoyl)indole-1-acetic acid. ture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium EXAMPLE 215 hydrogencarbonate solution and saturated brine, and dried N-(4-(3-(2-Chlorobenzoyl)-4,5-dimethylthiophen-2-yl)- over magnesium sulfate. The solvent was concentrated 5-methyl(1,2,4-triazol-3-ylmethyl)-N'-(2-chlorophenyl)urea under reduced pressure, and the obtained solid was crystal is obtained in the same manner as in Example 31 using lized from a small amount of ethyl acetate to give 1.1 g of 2-chlorophenyl isocyanate and 3-aminome thyl-4-(3-(2- ethyl (2-(4-(3-benzoyl-5-ethylthiophen-2-yl)-5-methyl(1.2. 4triazol-3-ylmethylcarbamoyl)indol-1-yl)acetate. chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-5-methyl(12.4 45 triazole. mp. 129°-131° C. EXAMPLE 216 EXAMPLE 221 N-(4-(3-(2-Chlorobenzoyl)-4,5-dimethylthiophen-2-yl)- Ethyl 2-(4-(3-benzoyl-5-ethylthiophen-2-yl)-5-methyl(1, 5-methyl(1.2.4 triazol-3-ylmethyl)-N'-(3-methylphenyl) 50 2,4triazol-3-ylmethylcarbamoyl)indole-1-acetate (0.74 g) urea is obtained in the same manner as in Example 31 using was subjected to alkali hydrolysis in the same manner as in 3-methylphenyl isocyanate and 3-aminomethyl-4-(3-(2- Example 19 to give 0.50 g of 2-(4-(3-benzoyl-5- chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-5-methyl(1.24) ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3- triazole. ylmethylcarbamoyl)indole-1-acetic acid. 55 m.p. 130° C. (decomposition) EXAMPLE 217 EXAMPLE 222 N-(4-(3-(2-Chlorobenzoyl)-4,5-dimethylthiophen-2-yl)- 2-Ethyl-9-methyl-4-phenyl-6H-thieno3.2-f 1.2.4) 5-methyl(1,2,4-triazol-3-ylmethyl)-N'-(3-methoxyphenyl) triazolo(43-a 1,4-diazepine is subjected to hydrolysis in urea is obtained in the same manner as in Example 31 using the same manner as in Example 89. and reacted with 3-methoxyphenyl isocyanate and 3-aminomethyl-4-(3-(2- 2-chlorophenyl isocyanate to give N-(4-(3-benzoyl-5- chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-5-methyl(1.24) ethylthiophen-2-yl)-5-methyl(1,2,4-triazol-3-ylmethyl)-N'- triazole. (2-chlorophenyl)urea. EXAMPLE 218 65 EXAMPLE 223 N-(4-(3-Benzoyl-5-ethylthiophen-2-yl)-5-methyl 12.4) 2-Ethyl-9-methyl-4-phenyl-6H-thieno3,2-f 1.2.4) triazol-3-ylmethyl)-3,4-dichlorobenzamide is obtained in triazolo43-a 1.4-diazepine is subjected to hydrolysis in 5,760,032 77 78 the same manner as in Example 89, and reacted with EXAMPLE 230 3-methylphenyl isocyanate to give N-(4-(3-benzoyl-5- 2-Ethyl-4-(2-fluorophenyl)-9-methyl-6H-thienol3.2-f ethylthiophen-2-yl)-5-methyl 12.4 triazol-3-ylmethyl)-N'- 1.2.4 triazolo43-a 14-diazepine is subjected to hydroly (3-methylphenyl)urea. sis in the same manner as in Example 226, and reacted with 3-methylphenyl isocyanate to give N-(4-(5-ethyl-3-(2- EXAMPLE 224 fluorobenzoyl)thiophen-2-yl)-5-methyl(1,2,4-triazol-3- 2-Ethyl-9-methyl-4-phenyl-6H-thieno3.2-f 1.24) ylmethyl)-N'-(3-methylphenyl)urea. triazolo43-a 1.4)diazepine is subjected to hydrolysis in the same manner as in Example 89, and reacted with EXAMPLE 231 3-methoxyphenyl isocyanate to give N-(4-(3-benzoyl-5- O ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-ylmethyl)-N'- 2-Ethyl-4-(2-fluorophenyl)-9-methyl-6H-thieno3.2-f (3-methoxyphenyl)urea. 1.2.4 triazolo43-a 1,4-diazepine is subjected to hydroly sis in the same manner as in Example 226, and reacted with EXAMPLE 2.25 3-methoxyphenyl isocyanate to give N-(4-(5-ethyl-3-(2- S fluorobenzoyl)thiophen-2-yl)-5-methyl(1,2,4-triazol-3- 2-Ethyl-4-(2-fluorophenyl)-9-methyl-6H-thieno3.2-f ylmethyl)-N'-(3-methoxyphenyl)urea. 1.24triazolo43-a 14-diazepine is subjected to hydroly sis in the same manner as in Example 226, and reacted with EXAMPLE 232 3,4-dichlorobenzoyl chloride to give N-(4-(5-ethyl-3-(2- 5-(2-Chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno2. fluorobenzoyl)thiophen-2-yl)-5-methyl 12.4) triazol-3- 3-e 1.4diazepine-2-thione (32 g) synthesized by the ylmethyl)-3,4-dichlorobenzamide. method disclosed in Arzneim-Forsch/Drug Res. 28 (I), EXAMPLE 226 Heft, 1153-1158 (1978) and dimethylaminoacetylhydrazide (12.3 g) were dissolved in toluene (300 ml), and the solution 2-Ethyl-4-(2-fluorophenyl)-9-methyl-6H-thieno3.2-f was stirred at room temperature for 5 hours. Then, acetic 1.2.4 triazolo 4.3-a 1,4-diazepine (500 mg) and 25 acid (9 g) was added to the reaction mixture, and the mixture p-toluenesulfonic acid monohydrate (874 mg) were dis was refluxed for 2 hours. The reaction mixture was washed solved in a mixed solvent (15 ml) of ethanol:water (9:1), and with a 5% aqueous sodium hydrogencarbonate solution and the solution was refluxed for 4 hours. The reaction mixture dried over magnesium sulfate. The solvent was evaporated, was concentrated under reduced pressure, and the obtained and the obtained residue was crystallized from ethyl acetate residue was dissolved in dimethylformamide (15 ml). 30 and isopropyl ether to give 26.3 g of 4-(2-chlorophenyl)-9- Indole-2-carbonyl chloride (407 mg) and triethylamine (1.07 dimethylaminomethyl-2-ethyl-6H-thienol 3.2-f 1,2,4) ml) were added, and the mixture was stirred at room triazolo43-a 1,4-diazepine. This compound (3.85 g) was temperature for one day. The reaction mixture was parti dissolved in a 5% aqueous hydrochloric acid solution (40 tioned between ethyl acetate and water. The organic layer ml), and the solution was stirred at 60° C. for 3 hours. Then, was washed with a saturated aqueous sodium hydrogencar 35 sodium hydrogencarbonate was added to the reaction mix bonate solution and saturated brine, and dried over magne ture to make the mixture alkaline. Chloroform (80 ml) and sium sulfate. The solvent was concentrated under reduced 3,4-dichlorobenzoyl chloride (2.3 g) were added, and the pressure, and the obtained solid was recrystallized from mixture was stirred under ice-cooling for 1 hour. The organic ethyl acetate to give 0.40 g of N-(4-(5-ethyl-3-(2- layer was washed with an aqueous citric acid solution, a fluorobenzoyl)thiophen-2-yl)-5-methyl(1,2,4-triazol-3- saturated aqueous sodium hydrogencarbonate solution and ylmethyl)indole-2-carboxamide. saturated brine, and dried over magnesium sulfate. The mp. 255°-256° C. solvent was evaporated, and the obtained crude product was recrystallized from ethyl acetate to give 2.22 g of N-(4-(3- EXAMPLE 227 45 (2-chlorobenzoyl)-5-ethylthiophe n-2-yl)-5- 2-Ethyl-4-(2-fluorophenyl)-9-methyl-6H-thieno3,2-f dimethylaminomethyl(1.2.4 triazol-3-ylmethyl)-3,4- 124triazolo43-a 1,4-diazepine is subjected to hydroly dichlorobenzamide. sis in the same manner as in Example 226, and reacted with mp. 186°-187° C. 1-ethoxycarbonylmethylindole-2-carbonyl chloride to give ethyl 2-(4-(5-ethyl-3-(2-fluorobenzoyl)thiophen-2-yl)-5- SO EXAMPLE 233 methyl 124triazol-3-ylmethylcarbamoyl)indole-1-acetate. N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- dimethylaminomethyl(1,2,4-triazol-3-ylmethyl)indole-2- EXAMPLE 228 carboxamide (1.83 g) was obtained in the same manner as in Ethyl 2-(4-(5-ethyl-3-(2-fluorobenzoyl)thiophen-2-yl)-5- Example 232 using indole-2-carbonyl chloride (1.97 g) and methyl(1,2,4-triazol-3-ylmethylcarbamoyl)indole-1-acetate 55 4-(2-chlorophenyl)-9-dimethylaminomethyl-2-ethyl-6H is subjected to alkali hydrolysis to give 2-(4-(5-ethyl-3-(2- thieno3.2-f 1.2.4 triazolo4.3-a 14-diazepine (3.85 g). fluorobenzoyl)thiophen-2-yl)-5-methyl(1,2,4-triazol-3- mp. 205°-207 C. ymethylcarbamoyl)indole-1-acetic acid. EXAMPLE 234 EXAMPLE 229 Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- 2-Ethyl-4-(2-fluorophenyl)-9-methyl-6H-thieno3.2-f dimethylaminomethyl(1,2,4-triazol-3-ylmethylcarbamoyl) 1.2.4 triazolo43-a 1.4-diazepine is subjected to hydroly indole-1-acetate is obtained in the same manner as in sis in the same manner as in Example 226, and reacted with Example 36 using 1-ethoxycarbonylmethylindole-2- 2-chlorophenyl isocyanate to give N-(2-chlorophenyl)-N'- 65 carbonyl chloride and 3-aminomethyl-4-(3-(2- (4-(5-ethyl-3-(2-fluorobenzoyl)thiophen-2-yl)-5-methyl 1, chlorobenzoyl)-5-ethylthiophen-2-yl)-5- 2,4-triazol-3-ylmethyl)urea. dimethylaminomethyl(1,2,4-triazole. 5,760,032 79 80 EXAMPLE 235 acetate is obtained in the same manner as in Example 36 Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- using 1-ethoxycarbonylmethylindole-2-carbonyl chloride dimethylaminomethyl(1,2,4-triazol-3-ylmethylcarbamoyl) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- indole-1-acetate is subjected to alkali hydrolysis to give ethylthiophen-2-yl)-5-isopropyl 12.4 triazole. 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- dimethylaminomethyl(1,2,4-triazol-3-ylmethylcarbamoyl) EXAMPLE 242 indole-1-acetic acid. Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- isopropyl. 1.2.4 triazol-3-ylmethylcarbamoyl)indole-1- EXAMPLE 236 acetate is subjected to alkali hydrolysis to give 2-(4-(3-(2- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-isopropyl 1.2.4 dimethylaminomethyl(1,2,4-triazol-3-ylmethyl)-N'-(2- triazol-3-ylmethylcarbamoyl)indole-1-acetic acid. chlorophenyl)urea is obtained in the same manner as in Example 31 using 2-chlorophenyl isocyanate and EXAMPLE 243 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- 15 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- yl)-5-dimethylaminomethyl(1,2,4-triazole. isopropyl(1,2,4-triazol-3-ylmethyl)-N'-(2-chlorophenyl) urea is obtained in the same manner as in Example 31 using EXAMPLE 237 2-chlorophenyl isocyanate and 3-aminomethyl-4-(3-(2- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-isopropyl 1.24) dimethylaminomethyl(1,2,4-triazol-3-ylmethyl)-N'-(3- 20 triazole. methylphenyl)urea is obtained in the same manner as in Example 31 using 3-methylphenyl isocyanate and EXAMPLE 244 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- yl)-5-dimethylaminomethyl 124triazole. isopropyl. 1,2,4-triazol-3-ylmethyl)-N'-(3-methylphenyl) urea is obtained in the same manner as in Example 31 using EXAMPLE 238 3-methylphenyl isocyanate and 3-aminomethyl-4-(3-(2- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-isopropyl 12.4 dimethylaminomethyl 12,4-triazol-3-ylmethyl)-N'-(3- triazole. methoxyphenyl)urea is obtained in the same manner as in Example 31 using 3-methoxyphenyl isocyanate and 30 EXAMPLE 245 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- yl)-5-dimethylaminomethyl(1,2,4-triazole. isopropyl(1,2,4-triazol-3-ylmethyl)-N'-(3-methoxyphenyl) urea is obtained in the same manner as in Example 31 using EXAMPLE 239 35 3-methoxyphenyl isocyanate and 3-aminomethyl-4-(3-(2- N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-isopropyl1.24) isopropyl 12.4 triazol-3-ylmethyl)-3,4-dichlorobenzamide triazole. is obtained in the same manner as in Example 36 using 3,4-dichlorobenzoyl chloride and 3-aminomethyl-4-(3-(2- Production Example 10 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-isopropyl 12.4 Production of ethyl (4-(2-chlorophenyl)-9-methyl-6H triazole. thieno 3.2-f 1.2.4 triazolo.4.3-a 14-diazepin-2-yl) EXAMPLE 240 carboxylate Using a known method such as Monatshefte fur Chemie, 4-(2-Chlorophenyl)-2-ethyl-9-isopropyl-6H-thieno3.2-f 45 104, 973-978 (1973), the compound was synthesized as 1,2,4-triazolo 4.3-a 1.4) diazepine (1.11 g) and follows. Potassium hydroxide (263.5 g) and a 40% methy p-toluenesulfonic acid monohydrate (1.71 g) were dissolved lamine aqueous solution (344 ml) were added to water (400 in a mixed solvent (25 ml) of ethanol and water (9:1), and ml). Carbon disulfide (240 ml) was dropwise added under the solution was refluxed for 3 hours. The reaction mixture ice-cooling, and the mixture was stirred for 1.5 hours. An was concentrated under reduced pressure, and the obtained 50 aqueous solution of chloroacetic acid (378 g), water (800 residue was dissolved in dimethylformamide (10 ml). ml) and potassium carbonate (276 g) was added, and the Indole-2-carbonyl chloride (1.06 g) and triethylamine (2.5 mixture was added to conc. hydrochloric acid (800 ml) with ml) were added, and the mixture was stirred at room vigorous stirring. The precipitated crystals were collected by temperature for one day. The reaction mixture was parti filtration, washed with water and dried to give 403 g of tioned between ethyl acetate and water. The organic layer 55 3-methyl-4-oxo-thiazolidine-2-thione. was washed with a saturated aqueous sodium hydrogencar 3-Methyl-4-oxo-thiazolidine-2-thione (403 g) and ethyl bonate solution and saturated brine, and dried over magne orthoformate (1370 ml) were added to acetic anhydride (775 sium sulfate. The solvent was concentrated under reduced m), and the mixture was refluxed for 6 hours. The mixture pressure, and the obtained solid was recrystallized from was allowed to stand, and the resulting crystals were col ethyl acetate to give 0.42 g of N-(4-(3-(2-chlorobenzoyl)- lected by filtration and washed with diisopropyl ether to give 5-ethylthiophen-2-yl)-5-isopropyl1.2.4 triazol-3-ylmethyl) 342 g of 5-ethoxymethylene-3-methyl-4-oxo-thiazolidine-2- indole-2-carboxamide. thione. mp. 2099-211° C. 5-Ethoxymethylene-3-methyl-4-oxo-thiazolidine-2- EXAMPLE 241 thione (422 g) was dissolved in dichloromethane (31). 65 3-(2-Chlorophenyl)-3-oxo-propionitrile (410.7 g) and tri Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- ethylamine (289.4 ml) were added under ice-cooling, and isopropyl 12.4)triazol-3-ylmethylcarbamoyl)indole-1- the mixture was stirred at room temperature overnight. 5,760,032 81 82 Then, the solvent was evaporated and ethyl acetate was product was dissolved in toluene (600 ml), and ethyl added. The precipitated crystals were collected by filtration orthoacetate (28.1 ml) was added. The mixture was stirred at and washed with ethyl acetate to give 692 g of 2-(2- 80° C. for 1 hour and concentrated. The resulting crystals chlorobenzoyl)-3-(3-methyl-4-oxo-2-thioxo-thiazolidine) were collected by filtration, washed with diisopropyl ether propionitrile. and recrystallized from a mixed solvent of ethyl acetate 2-(2-Chlorobenzoyl)-3-(3-methyl-4-oxo-2-thioxo diisopropyl ether to give 20.4 g of ethyl (4-(2- thiazolidine)propylnitrile (494 g) was added to a 15% aque chlorophenyl)-9-methyl-6H-thieno3.2-f 1.2.4 triazolo4. ous sodium hydroxide solution (2000 ml), and the mixture 3-a 14-diazepin-2-yl)carboxylate. was refluxed for 30 minutes. The mixture was cooled, and mp. 148°-150° C. the mixture was added to conc. hydrochloric acid (3000 ml). 10 Ethyl (4-(2-chlorophenyl)-9-methyl-6H-thieno3.2-f The precipitated crystals were collected by filtration and 124triazolo43-a 14-diazepin-2-yl)carboxylate can be washed with water to give 299 g of 5-amino-4-(2- also synthesized by the following method. chlorobenzoyl)thiophene-2-carboxylic acid. 2-Acetyl-4-(2-chlorophenyl)-9-methyl-6H-thieno3.2-f 5-Amino-4-(2-chlorobenzoyl)thiophene-2-carboxylic (1.24triazolo4.3-a 14-diazepine (1.0 g) synthesized by acid (24.0 g), potassium carbonate (176 g) and ethyl iodide 15 the method described in Artneim.-Forsch/Drug Res. 28 (II), (150 ml) were added to acetone (5 l), and the mixture was Heft 7, 1153-1158 (1978) was added to a 10% aqueous refluxed overnight. The solvent was evaporated, and ethyl sodium hypochlorite solution (21 ml), and the mixture was acetate and a saturated aqueous sodium hydrogencarbonate stirred at 60° C. for 1.5 hours. Sodium hydrogensulfite (2.9 solution were added. The precipitated layer was taken out, g) was added to the reaction mixture. Then, an aqueous citric washed with brine, dried over sodium sulfate and concen acid solution was added to adjust the reaction mixture to pH trated. The resulting crystals were collected by filtration and 3. The obtained crystals were collected by filtration, and washed with ethyl acetate to give 126 g of ethyl 5-amino washed with water to give 0.5 g of (4-(2-chlorophenyl)-9- 4-(2-chlorobenzoyl)thiophene-2-carboxylate. methyl-6H-thieno3.2-f 1.2.4 triazolo 4,3-a 1.4) Ethyl 5-amino-4-(2-chlorobenzoyl)thiophene-2- 25 diazepin-2-yl)carboxylic acid. carboxylate (280 g) and chloroacetyl chloride (218 ml) were The obtained (4-(2-chlorophenyl)-9-methyl-6H-thieno3, added to chloroform (4 D, and the mixture was refluxed 2-f 1.2.4 triazolo43-a 14-diazepin-2-yl)carboxylic acid under heating for 2.5 hours. Water was added thereto. The was dissolved in dimethylformamide. Potassium carbonate organic layer was taken out, and dried over magnesium and ethyl iodide were added, and the mixture was stirred sulfate. The solvent was evaporated. Then, diisopropyl ether overnight to give ethyl (4-(2-chlorophenyl)-9-methyl-6H was added, and the resulting crystals were collected by thieno3.2-f 1.2.4 triazolo.4.3-a 1.4 diazepin-2-yl) filtration and washed with diisopropyl ether to give 325g of carboxylate. ethyl 5-(2-chloroacetylamino)-4-(2-chlorobenzoyl) thiophene-2-carboxylate. EXAMPLE 246 Ethyl 5-(2-chloroacetylamino)-4-(2-chlorobenzoyl) 35 Ethyl (4-(2-chlorophenyl)-9-methyl-6H-thieno3,2-f thiophene-2-carboxylate (325 g) and sodium iodide (151.3 1.2.4 triazolo4.3-a) (14)diazepin-2-yl)carboxylate is g) were added to tetrahydrofuran (3500 ml), and the mixture hydrolyzed in the same manner as in Example 250, and was refluxed under heating for 1.5 hours. The mixture was reacted with 3,4-dichlorobenzoyl chloride to give ethyl cooled to -65 C., and ammonia (164 ml) was added. The ( 3 - (2 - c hl or o be n zo y ) - 2 - (3 - (3, 4 - reaction temperature was raised slowly to room temperature. dichlorobenzoylaminomethyl)-5-methyl 124triazol-4-yl) The solvent was evaporated, and chloroform and water were thiophen-5-yl)carboxylate. added. The organic layer was taken out, washed with water and dried over sodium sulfate. The solvent was evaporated. EXAMPLE 2.47 Toluene (71) and silica gel (1365g) were added thereto, and the mixture was refluxed under heating for 1.5 hours. The 45 Ethyl (4-(2-chlorophenyl)-9-methyl-6H-thieno 3.2-f silica gel was collected by filtration, and a mixed solvent of 1.24triazolo[4,3-a 14-diazepin-2-yl)carboxylate (0.5 g) chloroform-methanol (10:1) was added to elute the obtained and p-toluenesulfonic acid (0.75 g) were dissolved in a product. The solvent was evaporated, and ethyl acetate was mixed solvent (5 ml) of methanol:water (9:1), and the added. The resulting crystals were collected by filtration and solution was refluxed for 3.5 hours. The solvent was washed with ethyl acetate to give 70.0 g of ethyl (5-(2- SO evaporated, and the residue was dissolved in dimethylfor chlorophenyl)-1,2-dihydro-3H-thieno2.3-e) 1.4diazepin mamide (5 ml). Indole-2-carbonyl chloride (0.27 g) and 2-on-7-yl)-carboxylate. triethylamine (1.0 ml) were added under ice-cooling, and the Ethyl (5-(2-chlorophenyl)-1,2-dihydro-3H-thieno2,3-e mixture was stirred for 1 hour. The reaction mixture was 14ldiazepin-2-on-7-yl)carboxylate (40.0 g) and diphos partitioned between ethyl acetate and a saturated aqueous phorus pentasulfide (76.5 g) were added to chloroform (41), 55 sodium hydrogencarbonate solution. The organic layer was and the mixture was refluxed under heating for 2 hours. The washed with brine, an aqueous citric acid solution and brine, mixture was cooled, methanol (1 l) was added and the and dried over magnesium sulfate. The solvent was evapo insoluble matter was filtered off. The filtrate was washed rated. The residue was crystallized from ethyl acetate to give with a saturated aqueous sodium hydrogencarbonate solu 230 mg of ethyl (3-(2-chlorobenzoyl)-2-(3-(2- tion and dried over magnesium sulfate. The solvent was indolecarbonylaminomethyl)-5-methyl 12.4 triazol-4-yl) evaporated, and diisopropyl ether was added. The resulting thiophen-5-yl)carboxylate. crystals were collected by filtration and washed with diiso mp. 135°-140° C. propyl ether. The mixture was added to methanol (330 ml), and hydrazine monohydrate (16.4 ml) was added under EXAMPLE 248 ice-cooling with stirring. The mixture was further stirred at 65 Ethyl (4-(2-chlorophenyl)-9-methyl-6H-thieno 3.2-f room temperature for 1.5 hours. The obtained product was 1,2,4-triazolo 4,3-a 14-diazepin-2-yl)carboxylate is collected by filtration and washed with methanol. This hydrolyzed in the same manner as in Example 250, and 5,760,032 83 84 reacted with 2-chlorophenyl isocyanate to give ethyl (3-(2- indolecarbonylaminomethyl)-5-methyl 1.2.4 triazol-4-yl) chlorobenzoyl)-2-(3-(3-(2-chlorophenyl)ureidomethyl)-5- thiophen-5-yl)carboxylic acid. methyl 1.2.4 triazol-4-yl)thiophen-5-yl)carboxylate. EXAMPLE 253 EXAMPLE 249 (4-(2-Chlorophenyl)-9-methyl-6H-thieno3.2-f 1.2.4) Ethyl (4-(2-chlorophenyl)-9-methyl-6H-thieno3.2-f triazolo 4.3-a 14-diazepin-2-yl)carboxylic acid and 1.2.4 triazolo 4.3-a 14-diazepin-2-yl)carboxylate is p-toluenesulfonic acid are dissolved in a mixed solvent of hydrolyzed in the same manner as in Example 250, and methanol:water (9:1), and the solution is refluxed for 3 reacted with 3-methylphenyl isocyanate to give ethyl (3-(2- hours. The solvent is evaporated, and the residue is dissolved chlorobenzoyl)-2-(3-(3-(3-methylphenyl)ureidomethyl)-5- O in dimethylformamide. 2-Chlorophenyl isocyanate and tri methyl(1.2.4 triazol-4-yl)thiophen-5-yl)carboxylate. ethylamine are added under ice-cooing, and the mixture is stirred for 1 hour to give (3-(2-chlorobenzoyl)-2-(3-(3-(2- EXAMPLE 250 chlorophenyl)ureidomethyl)-5-methyl 12.4 triazol-4-yl) Ethyl (4-(2-chlorophenyl)-9-methyl-6H-thieno3.2-f thiophen-5-yl)carboxylic acid. 1.2.4 triazolo.4.3-a 1.4-diazepin-2-yl)carboxylate (4.0 g) 15 and p-toluenesulfonic acid monohydrate (6.0 g) were dis EXAMPLE 254 solved in a mixed solvent (40ml) of ethanol-water (9:1), and (3-(2-Chlorobenzoyl)-2-(3-(3-(3-methylphenyl) the mixture was refluxed under heating for 1 hour. The ureidomethyl)-5-methyl 12,4triazol-4-yl)thiophen-5-yl) solvent was evaporated, and the residue was dissolved in O carboxylic acid is obtained in the same manner as in dimethylformamide (40 ml). 3-Methoxyphenyl isocyanate Example 253 using (4-(2-chlorophenyl)-9-methyl-6H (1.44 ml) and triethylamine (8.3 ml) were added under thieno 3.2-f 1,2,4-triazolo 4.3-a 1.4-diazepin-2-yl) ice-cooling, and the mixture was stirred for 1 hour. The carboxylic acid and 3-methylphenyl isocyanate. reaction mixture was partitioned between ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution. 25 EXAMPLE 255 The organic layer was washed with brine, an aqueous citric acid solution and brine, and dried over magnesium sulfate. (4-(2-Chlorophenyl)-9-methyl-6H-thieno3.2-f 1.2.4 The solvent was evaporated. The residue was purified by triazolo43-a 1.4-diazepin-2-yl)carboxylic acid (0.47 g) silica gel column chromatography (developing solventiethyl and p-toluenesulfonic acid (0.76 g) were dissolved in a acetate) and recrystallized from ethyl acetate to give 2.18 g mixed solvent (5 ml) of methanol: water (9:1), and the of ethyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methoxyphenyl) 30 solution was refluxed for 1 hour. The solvent was ureidomethyl)-5-methyl 1.2.4 triazol-4-yl)thiophen-5-yl) evaporated, and the residue was dissolved in dimethylfor carboxylate. mamide (5 ml). 3-Methoxyphenyl isocyanate (0.19 ml) and m.p. 132-134 C. triethylamine (0.94 ml) were added under ice-cooling, and 35 the mixture was stirred for 30 minutes. Ethyl acetate was EXAMPLE 251 added thereto, and the mixture was extracted. An aqueous citric acid solution was added to adjust the reaction mixture Ethyl (3-(2-chlorobenzoyl)-2-(3- (3.4- to pH 3. The obtained crystals were collected by filtration dichlorobenzoylaminomethyl)-5-methyl 1,2,4-triazol-4-yl) and washed with water to give 0.42 g of (3-(2- thiophen-5-yl)carboxylate is hydrolyzed to give (3-(2- chlorobenzoyl)-2-(3-(3-(3-methoxyphenyl)ureidomethyl)- chlorobenzoyl)-2-(3-(3.4-dichlorobenzoylaminomethyl)-5- 5-methyl 124triazol-4-yl)thiophen-5-yl)carboxylic acid. methyl 12.4 triazol-4-yl)thiophen-5-yl)carboxylic acid. mp. 206-208 C. EXAMPLE 252 EXAMPLE 2.56 Ethyl (3-(2-chlorobenzoyl)-2-(3-(2- indolecarbonylaminomethyl)-5-methyl(1,2,4-triazol-4-yl) 45 3,4-Dichlorobenzoyl chloride and methyl (2-(3- thiophen-5-yl)carboxylate (0.16 g) was hydrolyzed using a aminomethyl-5-methyl 12.4 triazol-4-yl)-3-(2- 2M aqueous sodium hydroxide solution (0.22 ml) and chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methanol (1 ml) to give 0.053 g of (3-(2-chlorobenzoyl)-2- methyl (3-(2-chlorobenzoyl)-2-(3-(3.4- (3-(2-indolecarbonylaminomethyl)-5-methyl(1,2,4-triazol dichlorobenzoylaminomethyl)-5-methyl 124triazol-4-yl) 4-yl)thiophen-5-yl)carboxylic acid. thiophen-5-yl)acetate. m.p. 270° C. (decomposition) EXAMPLE 2.57 This compound can be also synthesized by the following method. Indole-2-carbonyl chloride and methyl (2-(3- (4-(2-Chlorophenyl)-9-methyl-6H-thieno3.2-f 1.24) 55 aminomethyl-5-methyl 12.4 triazol-4-yl)-3-(2- triazolo43-a 1,4-diazepin-2-yl)carboxylic acid (0.50 g) chlorobenzoyl)thiophen-5-yl)acetate are reacted to give was dissolved in a mixed solvent (5 ml) of methanol:water methyl (3-(2-chlorobenzoyl)-2-(3-(2- (9:1). p-Toluenesulfonic acid monohydrate (0.81 g) was indolecarbonylaminomethyl)-5-methyl 12,4triazol-4-yl) added, and the mixture was refluxed under heating for 3 thiophen-5-yl)acetate. hours. The solvent was evaporated, and dimethylformamide (5 ml), indole-2-carbonyl chloride (0.28 g) and triethylamine EXAMPLE 2.58 (1.0 ml) were added. The mixture was stirred for 1 hour. A 2-Chlorophenyl isocyanate and methyl (2-(3- saturated aqueous sodium hydrogencarbonate solution was aminomethyl-5-methyl 1.2.4 triazol-4-yl)-3-(2- added, and the mixture was extracted with ethyl acetate. The chlorobenzoyl)thiophen-5-yl)acetate are reacted to give extract was washed with an aqueous citric acid solution and 65 methyl (3-(2-chlorobenzoyl)-2-(3-(3-(2-chlorophenyl) brine, dried over magnesium sulfate and concentrated to ureidomethyl)-5-methyl(1.24) triazol-4-yl)thiophen-5-yl) give (3-(2-chlorobenzoyl)-2-(3-(2- acetate. 5,760,032 85 86 EXAMPLE 2.59 trated. The residue was purified by silica gel column chro matography (eluted with ethyl acetate and methanol), and 3-Methylphenyl isocyanate and methyl (2-(3- N-(2-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 12.4 aminomethyl-5-methyl 12.4 triazol-4-yl)-3-(2- triazolo 4.3-a) (1,4)diazepin-9-yl)ethyl)phthalimide was chlorobenzoyl)thiophen-5-yl)acetate are reacted to give obtained from a fraction containing the objective compound. methyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methylphenyl) This compound was dissolved in ethanol (200 ml). Hydra ureidomethyl)-5-methyl 1,2,4-triazol-4-yl)thiophen-5-yl) zine monohydrate (2.18 g) was added and the mixture was acetate. refluxed for 6 hours. The reaction mixture was concentrated, EXAMPLE 260 and partitioned between water and chloroform. The organic 10 layer was washed with saturated brine, and dried over 3-Methoxyphenyl isocyanate and methyl (2-(3- magnesium sulfate. The solvent was evaporated, and the aminomethyl-5-methyl 12.4 triazol-4-yl)-3-(2- obtained product was purified by silica gel column chroma chlorobenzoyl)thiophen-5-yl)acetate are reacted to give tography using a mixed solvent of chloroform and methanol methyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methoxyphenyl) as an eluent to give 5.2 g of 9-(2-aminoethyl)-4-(2- ureidomethyl)-5-methyl 1.2.4 triazol-4-yl)thiophen-5-yl) 15 chlorophenyl)-2-ethyl-6H-thieno3.2-f 124triazolo43 acetate. a 1,4-diazepine as an oil. 9-(2-Aminoethyl)-4-(2-chlorophenyl)-2-ethyl-6H-thieno EXAMPLE 2.61 3.2-f 12.4 triazolo43-a 1.4ldiazepine (1.0 g) thus Methyl (3-(2-chlorobenzoyl)-2-(3-(3.4- obtained, indole-2-carboxylic acid (0.455 g). Bop reagent dichlorobenzoylaminomethyl)-5-methyl 124triazol-4-yl) 2 (1.25 g) and triethylamine (0.75 g) were dissolved in dim thiophen-5-yl)acetate is subjected to hydrolysis to give ethylformamide (10 ml), and the solution was stirred over (3 - (2 - ch 1 or o be in Z oy 1) - 2 - (3 - (3, 4 - night. The reaction mixture was partitioned between ethyl dichlorobenzoylaminomethyl)-5-methyl(1,2,4-triazol-4-yl) acetate and water. The organic layer was washed with an thiophen-5-yl)acetic acid. aqueous citric acid solution, a saturated aqueous sodium 25 hydrogencarbonate solution and saturated brine, and dried EXAMPLE 2.62 over magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column Methyl (3-(2-chlorobenzoyl)-2-(3-(2- chromatography using a mixed solvent of ethyl acetate and indolecarbonylaminomethyl)-5-methyl(1.24triazol-4-yl) methanol as an eluent to give 0.68 g of N-(2-(4-(2- thiophen-5-yl)acetate is subjected to hydrolysis to give 30 chlorophenyl)-2-ethyl-6H-thieno3.2-fl 1.24triazolo43 (3-(2-chlorobenzoyl)-2-(3-(2-indolecarbonylaminomethyl)- a 14-diazepin-9-yl)ethyl)-indole-2-carboxamide. 5-methyl(1,2,4-triazol-4-yl)thiophen-5-yl)acetic acid. mp. 1749-178° C. EXAMPLE 2.63 EXAMPLE 267 Methyl (3-(2-chlorobenzoyl)-2-(3-(3-(2-chlorophenyl) 35 4-(2-Chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9- ureidomethyl)-5-methyl 1.2.4 triazol-4-yl)thiophen-5-yl) methyl-6H-thieno 3.2-f 1.2.4 triazolo 4.3-a 1.4) acetate is subjected to hydrolysis to give (3-(2- diazepine described in Example 1 of Japanese Patent Pub chlorobenzoyl)-2-(3-(3-(2-chlorophenyl)ureidomethyl)-5- lication No. 55510/1993 was dissolved in a 5% aqueous methyl 12.4 triazol-4-yl)thiophen-5-yl)acetic acid. hydrochloric acid solution, and the solution was stirred at 60° C. for 5 hours. A saturated aqueous sodium hydrogen EXAMPLE 264 carbonate solution was added to the reaction mixture to make the mixture alkaline. Chloroform and 3,4- Methyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methylphenyl) dichlorobenzoyl chloride were added, and the mixture was ureidomethyl)-5-methyl 1.2.4 triazol-4-yl)thiophen-5-yl) stirred under ice-cooling for 1 hour. The organic layer was acetate is subjected to hydrolysis to give (3-(2- 45 washed with an aqueous citric acid solution, a saturated chlorobenzoyl)-2-(3-(3-(3-methylphenyl)ureidomethyl)-5- aqueous sodium hydrogenicarbonate solution and saturated methyl 12.4 triazol-4-yl)thiophen-5-yl)acetic acid. brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified to give N-(4-(3-(2- EXAMPLE 265 chlorobenzoyl)-5-(2-(4-isobutylphenyl)ethyl)thiophen-2- Methyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methoxyphenyl) 50 yl)-5-methyl(1,2,4-triazol-3-ylmethyl)-3,4-dichlorobenza ureidomethyl)-5-methyl 1.2.4 triazol-4-yl)thiophen-5-yl) mide. acetate is subjected to hydrolysis to give (3-(2- chlorobenzoyl)-2-(3-(3-(3-methoxyphenyl)ureidomethyl)- EXAMPLE 268 5-methyl(1,2,4-triazol-4-yl)thiophen-5-yl)acetic acid. N-(2-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2, 55 4triazolo 4.3-a 1.4)diazepin-9-yl)ethyl)-3,4- EXAMPLE 2.66 dichlorobenzamide (0.98 g) was obtained in the same man 5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-1,3-dihydro ner as in Example 59 using 9-(2-aminoethyl)-4-(2- 2H-thieno2,3-e 1,4-diazepine (15.9 g) was suspended in chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo43 chloroform (200 ml) under ice-cooling. a 1,4-diazepine (2.0 g), dichloroethane (100 ml), 3-Phthalimidepropionyl chloride (12.5g) was added, and the triethylamine (0.79 ml) and 3,4-dichlorobenzoyl chloride mixture was stirred for 1 hour. The reaction mixture was (1.18 g). washed with a saturated aqueous sodium hydrogencarbonate mp. 141°-142° C. solution and dried over magnesium sulfate. The solvent was evaporated. The residue was dissolved in a mixed solvent of 65 EXAMPLE 269 toluene (150 ml) and acetic acid (4.5 ml), and the solution 5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-1,3-dihydro was refluxed for 3 hours. The reaction mixture was concen 2H-thieno 2,3-e 1.4-diazepine (9.56 g) was suspended in 5,760,032 87 88 chloroform (100 ml) under ice-cooling. solution and saturated brine and dried over magnesium 4-Phthalimidebutanoyl chloride (7.93 g) was added, and the sulfate. The solvent was evaporated to give 1.01 g of mixture was stirred for 1 hour. The reaction mixture was cyclohexyl (S)-3-amino-3-(4-(2-chlorophenyl)-2-ethyl-6H washed with a saturated aqueous sodium hydrogencarbonate thieno3.2-f 1,2,4-triazolo 4.3-a 1.4ldiazepin-9-yl) solution and dried over magnesium sulfate. The solvent was 5 propionate. evaporated. The residue was dissolved in a mixed solvent of Cyclohexyl (S)-(+)-3-(3,4-dichlorobenzoylamino)-3-(4- toluene (200 ml) and acetic acid (2.7 ml) and the mixture (2-chlorophenyl)-2-ethyl-6H-thieno 3.2-f 1,2,4-triazolo4. was refluxed for 3 hours. The reaction mixture was concen 3-a 1.4-diazepin-9-yl)propionate (0.43 g) was obtained in trated and the residue was purified by silica gel column the same manner as in Example 59 using cyclohexyl (S)-3- chromatography (eluted with ethyl acetate and methanol) to 10 (4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo give 10.13 g of 4-(2-chlorophenyl)-2-ethyl-9-(3- 43-a 14-diazepin-9-yl)propionate (1.01 g) thus obtained, phthalimidepropyl)-6H-thieno3.2-f 1,2,4-triazolo43-a dichloroethane (50 ml), triethylamine (0.30 ml) and 3,4- 1.4-diazepine. dichlorobenzoyl chloride (0.45 g). 4-(2-Chlorophenyl)-2-ethyl-9-(3-phthalimidepropyl)-6H m. p. 165-166° C., or = +61.3 (c= 1 . thieno3.2-f 1,2,4-triazolo4.3-a 14-diazepine (4.64 g) 5 dimethylformamide) thus obtained was dissolved in ethanol (90 ml). Hydrazine monohydrate (0.87 ml) was added, and the mixture was EXAMPLE 271 refluxed for 2.5 hours. The reaction mixture was filtered, and Cyclohexyl (S)-(+)-3-(3,4-dichlorobenzoylamino)-3-(4- the solvent was evaporated. Water was added, and the (2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo4, mixture was extracted with chloroform. The extract was 3-a 1,4-diazepin-9-yl)propionate (0.40 g) obtained in washed with saturated brine and dried over magnesium Example 270 was dissolved in methanol (5 ml). A 2N sulfate. The solvent was evaporated, and the residue was aqueous sodium hydroxide solution (0.6 ml) was added, and purified by silica gel column chromatography using a mixed the mixture was stirred for 3 hours. The solvent was evapo solvent of chloroform and methanol as an eluent to give 1.67 rated. Water was added and the mixture was washed with g of 9-(3-aminopropyl)-4-(2-chlorophenyl)-2-ethyl-6H 25 ethyl acetate. Citric acid was added to the aqueous layer to thieno3,2-f 1,2,4-triazolo.4,3-a 14-diazepine. make the layer acidic. The mixture was extracted with ethyl N-(3-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2, acetate and the extract was dried over magnesium sulfate. 4triazolo 4.3-a 1.4 diazepin-9-yl)propyl)-3,4- The solvent was evaporated, and the residue was purified by dichlorobenzamide (0.87 g) was obtained in the same man silica gel column chromatography using a mixed solvent of ner as in Example 268 using 9-(3-aminopropyl)-4-(2- chloroform, methanol and acetic acid as an eluent to give 96 chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo43 mg of (S)-(+)-3-(3,4-dichlorobenzoylamino)-3-(4-(2- a 1.4)diazepine (1.67 g) thus obtained, dimethylformamide chlorophenyl)-2-ethyl-6H-thieno3.2-f 124triazolo43 (80 ml), triethylamine (0.64 ml) and 3.4-dichlorobenzoyl a 14-diazepin-9-yl)propionic acid. chloride (0.95 g). 35 NMR (270 MHz, CDOD):1.23(3H,t.J-7.4 Hz), 2.81(2H, m.p. 143°-144° C. qJ=7.4 Hz), 3.08-3.45(2H,m), 5.93-5.96(1Him), 6.06(1H, EXAMPLE 270 s), 6.45(1Hs), 7.367.93(8H,m) (o)=+65.5° (c=1, dimethylformamide) B-Cyclohexyl N-o-tert-butoxycarbonyl-L-aspartate (4.0 g) was dissolved in tetrahydrofuran (50 ml), and triethy EXAMPLE 272 lamine (1.8 ml) was added. Isobutyl chloroformate (1.6 ml) Cyclohexyl (R)-(-)-3-(3,4-dichlorobenzoylamino)-3-(4- was gradually added dropwise under cooling with ice-salt. (2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1,2,4-triazolo4, Thirty minutes later, 5-(2-chlorophenyl)-7-ethyl-2- 3-a 14-diazepin-9-yl)propionate (0.73 g) was obtained in hydrazine-3H-thieno,2,3-e (1.4diazepine (2.0 g) was dis the same manner as in Example 270 using B-cyclohexyl solved in dimethylformamide (20 ml), and the solution was 45 N-O-tert-butoxycarbonyl-D-aspartate (5.0 g), tetrahydrofu dropwise added to the mixture. The mixture was stirred at ran (80 ml), triethylamine (2.2 ml), isobutyl chloroformate room temperature. Ethyl acetate was added to the reaction (2.1 ml) and 5-(2-chlorophenyl)-7-ethyl-2-hydrazine-3H mixture. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and dried over thieno2,3-e 1,4-diazepine (3.4 g). magnesium sulfate. The solvent was evaporated, and the m. p. 170°-171° C., ol=-64.90 (c=1, residue was dissolved in toluene (60 ml). Acetic acid (1 ml) dimethylformamide) was added, and the mixture was refluxed for 5 hours. Ethyl EXAMPLE 273 acetate was added to the reaction mixture. The mixture was washed with a saturated aqueous sodium hydrogencarbonate (R)-(-)-3-(3,4-Dichlorobenzoylamino)-3-(4-(2- solution and dried over magnesium sulfate. The solvent was 55 chlorophenyl)-2-ethyl-6H-thieno3.2-fl 1.2.4 triazolo43 evaporated, and the residue was purified by silica gel column a 1,4-diazepin-9-yl)propionic acid (67 mg) was obtained in chromatography using ethyl acetate as an eluent to give 1.26 the same manner as in Example 271 using cyclohexyl g of cyclohexyl (S)-3-(tert-butoxycarbonylamino)-3-(4-(2- (R)-(-)-3-(3,4-dichlorobenzoylamino)-3-(4-(2- chlorophenyl)-2-ethyl-6H-thieno3.2-fl 1.24triazolo 4.3- chlorophenyl)-2-ethyl-6H-thieno3.2-f 12.4 triazolo43 a 1,4-diazepin-9-yl)propionate. a 14-diazepin-9-yl)propionate (0.50 g) obtained in Cyclohexyl (S)-3-(tert-butoxycarbonylamino)-3-(4-(2- Example 272, methanol (5 ml) and a 2N sodium hydroxide chlorophenyl)-2-ethyl-6H-thieno 3.2-f 124triazolo43 aqueous solution (0.7 ml). a 14-diazepin-9-yl)propionate (1.26 g) obtained was dis O)--67.0° (c=1, dimethylformamide) solved in trifluoroacetic acid (13 ml), and the solution was stirred under ice-cooling for 30 minutes. The solvent was EXAMPLE 274 evaporated, and chloroform was added. The mixture was Cyclohexyl (S)-(+)-4-(3,4-dichlorobenzoylamino)-4-(4- washed with a saturated aqueous sodium hydrogencarbonate (2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo.4, 5,760,032 89 90 3-a 14-diazepin-9-yl)butanoate (1.22 g) was obtained in solution and saturated brine, and dried over magnesium the same manner as in Example 270 using Y-cyclohexyl sulfate. The solvent was evaporated, and the residue was N-o-tert-butoxycarbonyl-L-glutamate (4.1 g), tetrahydrofu purified by silica gel column chromatography using ethyl ran (50 ml), triethylamine (1.8 ml), isobutyl chloroformate acetate as an eluent to give 30.1 g of benzyl (R)-4-(4-(2- (1.6 ml) and 5-(2-chlorophenyl)-7-ethyl-2-hydrazine-3H 5 chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolol.43 thieno2,3-e 14-diazepine (2.0 g). a 1.4-diazepin-9-yl)-4-(tert-butoxycarbonylamino) m. p. 157-159 C., o= +7 0.2° (c= 1. butanoate. dimethylformamide) Benzyl (R)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2- f 1.2.4 triazolo 4.3-a 1.4) diazepin-9-yl)-4-(tert EXAMPLE 275 O butoxycarbonylamino)butanoate (3.14 g) thus obtained was dissolved in trifluoroacetic acid (35 ml), and the solution (S)-(+)-4-(3,4-Dichlorobenzoylamino)-4-(4-(2- was stirred under ice-cooling for 30 minutes. The solvent chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo43 was evaporated, and chloroform was added. The mixture a 14-diazepin-9-yl)butanoic acid (0.40 g) was obtained in was washed with a saturated aqueous sodium hydrogencar the same manner as in Example 271 using cyclohexyl 5 bonate solution and saturated brine, and dried over magne (S)-(+)-4-(3,4-dichlorobenzoylamino)-4-(4-(2- sium sulfate. The solvent was evaporated, and the residue chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24triazolo43 was dissolved in ethyl acetate. A solution of a 14-diazepin-9-yl)butanoate (1.0 g) obtained in Example p-toluenesulfonic acid monohydrate (1.82 g) in ethanol was 274, methanol (10 ml) and a 2N sodium hydroxide aqueous added, and the precipitated crystals were collected by fil solution (1.7 ml). tration to give 3.42 g of benzyl (R)-4-amino-4-(4-(2- NMR (270 MHz, CDC1):1.29(3H,t.J=7.3 Hz), 241-2.54 chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24triazolo[4,3- (4H.m), 2.81(2H.qJ=7.3 Hz), 4.69-5.11(2H.m). 5.93-5.96 a 1.4ldiazepin-9-yl)butanoate di-p-toluenesulfonate. (1H.m), 7.26(1Hs), 7.30-7.92(7H,m), 8.98(1H.m) ol--84.3 (c=1, dimethylformamide) EXAMPLE 278 25 Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H EXAMPLE 276 thieno3.2-f 1.2.4 triazolo 4,3-a 1.4-diazepin-9-yl) Cyclohexyl (R)-(-)-4-(3,4-dichlorobenzoylamino)-4-(4- butanoate di-p-toluenesulfonate (3.0 g) and triethylamine (2-chlorophenyl)-2-ethyl-6H-thieno3.2-fl 1.2.4 triazolo.4, (1.46 ml) were dissolved in dichloroethane (50 ml). Indole 3-a 14-diazepin-9-yl)butanoate (0.92 g) was obtained in 2-carbonyl chloride (923 mg) was added, and the mixture the same manner as in Example 270 using Y-cyclohexyl 30 was stirred at room temperature for 1 hour. Chloroform was N-o-tert-butoxycarbonyl-D-glutamate (5.0 g), tetrahydrofu added to the reaction mixture. The mixture was washed with ran (80 ml), triethylamine (2.1 ml), isobutyl chloroformate a 10% aqueous citric acid solution, a saturated aqueous (2.1 ml) and 5-(2-chlorophenyl)-7-ethyl-2-hydrazine-3H sodium hydrogencarbonate solution and saturated brine, and thieno2,3-e 1,4-diazepine (3.2 g). 35 dried over magnesium sulfate. The solvent was concentrated m. p. 158-160° C.. O = -70.9 (c= 1, under reduced pressure, and the residue was purified by dimethylformamide) silica gel column chromatography using ethyl acetate as an eluent to give 1.44 g of benzyl (R)-4-(4-(2-chlorophenyl)- 2-ethyl-6H-thieno3.2-f 1.2.4 triazolo 4.3-a 1.4 EXAMPLE 277 diazepin-9-yl)-4-(1H-indole-2-carboxamide)butanoate. (R)-(-)-4-(3,4-Dichlorobenzoylamino)-4-(4-(2- chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24triazolo.43 NMR (270 MHz. DMSO-d):1.07(3H.t.J=7.9 Hz), a 14-diazepin-9-yl)butanoic acid (0.36 g) was obtained in 2.3-2.8(6H), 4.80(2H,bs). 5.08(2H,s), 5.68(1H.m), 6.36(1H, the same manner as in Example 271 using cyclohexyl s), 7.03(1H.t.J=7.3 Hz), 7.10-7.55(12H), 7.59(1H.d.J=5.3 (R)-(-)-4-(3,4-dichlorobenzoylamino)-4-(4-(2- Hz).9.06(1H.m), 11.58(1Hs) chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24triazolo43 45 EXAMPLE 279 a 1,4-diazepin-9-yl)butanoate (0.7 g) obtained in Example Cyclohexyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl 276, methanol (7 ml) and a 2N sodium hydroxide aqueous 6H-thieno3.2-f 1.24triazolo[4,3-a 1.4-diazepin-9-yl) solution (1 ml). butanoate (6.57 g) was synthesized in the same manner as in ol--82.1 (c=1. dimethylformamide) 50 Example 270 using y-cyclohexyl N-o-tert-butoxycarbonyl D-glutamate (10.0 g), tetrahydrofuran (97 ml), triethylamine Production Example 11 (4.6 ml), isobutyl chloroformate (4.7 ml) and 5-(2- Y-Benzyl N-o-tert-butoxycarbonyl-L-aspartate (25.0 g) chlorophenyl)-7-ethyl-2-hydrazine-3H-thieno2.3-e 1.4) was dissolved intetrahydrofuran (250 ml), and triethylamine diazepine (9.7 g). (11.4 ml) was added. Isobutyl chloroformate (10.7 ml) was 55 Cyclohexyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl gradually added dropwise at -10°C. Thirty minutes later, a 6H-thieno3.2-f 1.24triazolo43-a 1.4-diazepin-9-yl) solution of 5-(2-chlorophenyl)-7-ethyl-2-hydrazino-3H butanoate (2.77 g) thus obtained and indole-2-carboxylic thieno2,3-e 1.4-diazepine (23.65 g) dissolved in dimeth acid (1.0 g) were dissolved in dimethylformamide (30 ml). ylformamide (50 ml) was dropwise added to the reaction Triethylamine (1.5ml) and Bop reagent (2.65 g) were added, mixture. The mixture was stirred at room temperature. Ethyl and the mixture was stirred for 4 hours. The reaction mixture acetate was added to the reaction mixture. The mixture was was partitioned between ethyl acetate and water. The organic washed with a saturated aqueous sodium hydrogencarbonate layer was washed with an aqueous citric acid solution, solution and dried over magnesium sulfate. The solvent was saturated brine, a saturated aqueous sodium hydrogencar evaporated, and the residue was dissolved in toluene (1500 bonate solution and saturated brine, and dried over magne ml). Acetic acid (25 ml) was added, and the mixture was 65 sium sulfate. The solvent was evaporated, and the residue refluxed for 5 hours. The reaction mixture was cooled, was purified by silica gel column chromatography using washed with a saturated aqueous sodium hydrogencarbonate ethyl acetate as an eluent to give 1.87 g of cyclohexyl 5,760,032 91 92 (R)-(-)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f toluenesulfonate (3.0 g), 2-amino-4-chlorobenzoic acid 1.2.4 triazolo 4.3-a 1.4-diazepin-9-yl)-4-(indole-2- (0.66 g), dimethylformamide (30 ml), triethylamine (1.94 carboxamide)butanoate. ml) and Bop reagent (1.69 g). m. p. 133-137 C.. O = -91.9 (c= 1, NMR (270 MHz, DMSO-d):1.08(3H,t.J=7.5 Hz). dimethylformamide) 2.24-2.59(4H.m), 2.71(2H.q.J=7.5 Hz), 4.81(2H,s), 5.03-5. 13(2H.q), 5.51-5.59(1H.q). 6.39(1Hs), 6.41-7.48 EXAMPLE 280 (12H.m), 8.81-8.83(1H,d) (R)-(-)-4-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f ol--53.6° (c=1, dimethylformamide) (1,2,4-triazolof 4.3-a 1.4 diazepin-9-yl)-4-(indole-2- O carboxamide)butanoic acid (0.37 g) was obtained in the EXAMPLE 2.84 same manner as in Example 271 using cyclohexyl (R)-(-)- (R)-(-)-4-(2-Amino-4-chlorobenzoylamino)-4-(4-(2- 4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 chlorophenyl)-2-ethyl-6H-thieno3.2-f 1,2,4-triazolo43 triazolo 4.3-a 1.4 diazepin-9-yl)-4-(1H-indole-2- a 14-diazepin-9-yl)butanoic acid (0.23 g) was obtained in carboxamide)butanoate (1.42 g) obtained in Example 279, 15 the same manner as in Example 271 using benzyl (R)-(-)- methanol (14 ml) and a 2N sodium hydroxide aqueous 4-(2-amino-4-chlorobenzoylamino)-4-(4-(2-chlorophenyl)- solution (2 ml). 2-ethyl-6H-thieno 3.2-f 1.2.4 triazolo 4.3-a 1.4 m.p. 276°-283° C. (dec.), ol=-115.8° (c=1, diazepin-9-yl)butanoate (1.28 g), methanol (13 ml) and a 2N dimethylformamide) sodium hydroxide aqueous solution (1.9 ml). 20 NMR (270 MHz, DMSO-d):1.11(3H,t.J=7.5 Hz). EXAMPLE 281 2.22-2.42(4H.m). 2.74(2H.q.J=7.5 Hz). 4.82(2H,s), Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H 5.51-5.53(1H,q), 6.39(1H,s), 6.42-746(7H.m), 8.86(1H,d) thieno,3,2-f 1,2,4-triazolo(4.3-a) (1,4)diazepin-9-yl) O=-314 (c-1. dimethylformamide) butanoate di-p-toluenesulfonate (3.0 g) and 3-quinolinecarboxylic acid (0.66 g) were dissolved in DMF 25 Production Example 12 (30 ml). Triethylamine (1.94 ml) and Bop reagent (1.69 g) 9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno3, were added and the mixture was stirred. Water was added to 2-f 1,2,4-triazolo 4.3-all 14ldiazepine (20 g) was dis the reaction mixture. The mixture was washed with an solved in chloroform (200 ml), tert-Butyl dicarbonate (13.4 aqueous citric acid solution, saturated brine, a saturated 30 g) was added under ice-cooling, and the mixture was stirred aqueous sodium hydrogencarbonate solution and saturated at room temperature for 4 hours. The mixture was washed brine, and dried over magnesium sulfate. The solvent was with a saturated aqueous sodium hydrogen-carbonate solu evaporated, and the residue was purified by silica gel column tion and saturated brine, and dried over magnesium sulfate. chromatography using a mixed solvent of ethyl acetate and The solvent was evaporated, and the residue was recrystal methanol as an eluent to give 1.76 g of benzyl (R)-(-)-4- lized from a mixed solvent of ethyl acetate and hexane to (4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24triazolo 35 give 23.85 g of 9-(tert-butoxycarbonylaminomethyl)-4-(2- 4.3-a 1.4 diazepin-9-yl)-4-(quinoline-3-carboxamide) chlorophenyl)-2-ethyl-6H-thieno3.2-f 12.4 triazolo43 butanoate. a 14ldiazepine. NMR (270 MHz. DMSO-d):1.05(3H,t.J=7.4 Hz), 9- (tert-Butoxycarbonylaminomethyl)-4-(2- 2.25-2.54(4H.m), 2.70(2H.q.J=7.4 Hz), 5.09(2H.s), chlorophenyl)-2-ethyl-6H-thieno 3.2-f 1,2,4-triazolo(43 5.70-5.75(1H.q),637(1H,s), 7.29–8.10(13.H.m), 8.77(1H, a 14ldiazepine (21.79 g) thus obtained was dissolved in s), 9.22(1Hs), 9.43(1H.s) THF (220 ml), A2N lithium diisopropylamide-hexane solu ol--83.6° (c=1, dimethylformamide) tion (49.8 ml) was dropwise added at -78° C., and the mixture was stirred for 1 hour. Ethyl bromoacetate (5.8 ml) EXAMPLE 282 was added. The reaction temperature was raised slowly to (R)-(-)-4-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f room temperature, and the mixture was stirred for 2 hours. 1.2.4 triazolo 4,3-a 14-diazepin-9-yl)-4-(quinoline-3- A saturated aqueous ammonium chloride solution was added carboxamide)butanoic acid (0.32 g) was obtained in the to the reaction mixture. The mixture was extracted with same manner as in Example 271 using benzyl (R)-(-)-4-(4- ethyl acetate. The extract was washed with saturated brine, (2-chlorophenyl)-2-ethyl-6H-thieno 3.2-f 1.24triazolo.4, 50 and dried over magnesium sulfate. The solvent was 3-a 1.4-diazepin-9-yl)-4-(quinoline-3-carboxamide) evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and butanoate (1.65 g), methanol (16.5 ml) and a 2N sodium hexane as an eluent to give 3.91 g of ethyl 9-(tert hydroxide aqueous solution (2.4 ml). butoxycarbonylaminomethyl)-4-(2-chlorophenyl)-2-ethyl NMR (270 MHz, DMSO-d):1.08(3H.t.J=7.3 Hz), 55 6H-thieno3.2-f 1.2.4 triazolo(43-a 1.4)-diazepine-6- 2.32-2.68(4H.m). 2.75(2H.q.J=7.3 Hz), 4.91 (2H.s), acetate. 5.70-5.71(1H,q), 6.37(1H,s), 7.34-8.10(8Him), 8.77(1Hs), Ethyl 9-(tert-butoxycarbonylaminomethyl)-4-(2- 9.21(1H,s), 9.40(1H,d) chlorophenyl)-2-ethyl-6H-thieno3.2-f 124triazolo.43 O)=-102.3 (c=1, dimethylformamide) a 14-diazepine-6-acetate (3.91 g) thus obtained was dis solved in trifluoroacetic acid (40 ml), and the solution was EXAMPLE 283 stirred under ice-cooling. The solvent was evaporated and Benzyl (R)-(-)-4-(2-amino-4-chlorobenzoylamino)-4-(4- chloroform was added. The mixture was washed with a (2-chlorophenyl)-2-ethyl-6H-thieno 3.2-f 1,2,4-triazolo.4, Saturated aqueous sodium hydrogencarbonate solution and 3-a 1.4-diazepin-9-yl)butanoate (1.73 g) was obtained in saturated brine, and dried over magnesium sulfate. The the same manner as in Example 281 using benzyl (R)-4- 65 solvent was evaporated to give 2.55 g of ethyl amino-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2. 9-(aminomethyl)-4-(2-chlorophenyl)-2-ethyl-6H-thieno3. 4triazolo 4.3-a 1,4-diazepin-9-yl)butanoate di-p- 2-f 1,2,4-triazolo 4.3-a) 1.4-diazepine-6-acetate. 5,760,032 93 94 EXAMPLE 285 citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over mag Ethyl 9-(aminomethyl)-4-(2-chlorophenyl)-2-ethyl-6H nesium sulfate. The solvent was evaporated. The residue was thieno3.2-f 1.2.4 triazolo 4,3-a 14-diazepine-6-acetate purified by silica gel column chromatography using a mixed (1.2 g) obtained in Production Example 12 and 3,4- solvent of ethyl acetate and methanol (10:1) as an eluent, dichlorobenzoyl chloride (0.59 g) were dissolved in dichlo and crystallized from isopropyl ether to give 0.95 g of roethane (60 ml). Triethylamine (0.40ml) was added and the tert-butyl 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- mixture was stirred for 1 hour. The reaction mixture was yl)-5-methyl(1,2,4-triazol-3-ylmethyl)ureido)benzoate. washed with an aqueous citric acid solution, saturated brine, mp. 1949-195° C. a saturated aqueous sodium hydrogencarbonate solution and 10 saturated brine, and dried over magnesium sulfate. The EXAMPLE 289 solvent was evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate as an tert-Butyl 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen eluent to give 0.88g of ethyl 9-((3,4-dichlorobenzoylamino) 2-yl)-5-methyl 1.2.4 triazol-3-ylmethyl)ureido)benzoate methyl)-4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2, (800 mg) was dissolved in formic acid (20 ml), and the 4triazolo 4.3-a 14-diazepine-6-acetate. 15 solution was allowed to stand for one day. The reaction mp. 183°-184° C. mixture was concentrated, and the obtained crude crystals were recrystallized from isopropyl alcohol to give 580 mg of EXAMPLE 286 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- Ethyl 9-((3,4-dichlorobenzoylamino)methyl)-4-(2- methyl 12,4-triazol-3-ylmethyl)ureido)benzoic acid. chlorophenyl)-2-ethyl-6H-thieno3.2-f 1,2,4-triazolo43 mp. 178°-180° C. a 14-diazepine-6-acetate (0.4 g) was dissolved in metha EXAMPLE 290 nol (4 ml). 2N Sodium hydroxide (1 ml) was added and the mixture was stirred. The solvent was evaporated. Water was Ethyl indole-2-carboxylate (6.0 g) was dissolved in dim added and the mixture was washed with ethyl acetate. Citric 25 ethylformamide (60 ml) and sodium hydride (60% in oil, 1.4 acid was added to the aqueous layer to make the layer acidic. g) was added under ice-cooling. After stirring for 30 The solution was extracted with ethyl acetate and the extract minutes, bromoacetonitrile (2.3 ml) was added and the was dried over magnesium sulfate. The solvent was mixture was stirred. Water was added to the reaction evaporated, and the residue was recrystallized from a mixed mixture, and the mixture was extracted with ethyl acetate. solvent of diisopropyl alcohol and methanol to give 0.17 g 30 The extract was washed with saturated brine and dried over of 9-((3,4-dichlorobenzoylamino)methyl)-4-(2- magnesium sulfate. The solvent was evaporated, and the chlorophenyl)-2-ethyl-6H-thieno3.2-f 1,2,4-triazolo43 residue was recrystallized from ethyl acetate to give 6.6 g of a) (1,4)-diazepine-6-acetic acid isopropyl alcoholate. ethyl 1-cyanomethylindole-2-carboxylate. mp. 1679-169° C. m.p. 92°-94° C. 35 Ethyl 1-cyanomethylindole-2-carboxylate (5.35 g) EXAMPLE 287 obtained was dissolved in dimethylformamide (55 ml). Ethyl 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) Sodium azide (1.68 g) and ammonium chloride (1.38 g) -5-methyl(1,2,4-triazol-3-ylmethyl)ureido)benzoate (130 were added and the mixture was stirred at 80° C. for 2.5 mg) was obtained in the same manner as in Example 193 hours. Water was added to the reaction mixture and the using ethyl 3-aminobenzoate (0.15 ml), N,N'- 40 mixture was washed with ethyl acetate. Citric acid was carbonyldiimidazole (170 mg), 3-aminomethyl-4-(3-(2- added, and the mixture was extracted with ethyl acetate and chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12,4) the extract was dried over magnesium sulfate. The solvent triazole di-p-toluenesulfonate (0.74 g) and triethylamine was evaporated, and the residue was recrystallized from ethyl acetate to give 3.61 g of ethyl 1-(1H-tetrazol-5-yl) (1.4 ml). 45 mp. 1859-187° C. methylindole-2-carboxylate. mp. 1659-170° C. EXAMPLE 288 Ethyl 1-(1H-tetrazol-5-yl)methylindole-2-carboxylate tert-Butyl 3-(N-benzyloxycarbonylamino)benzoate (2.18 (1.17 g) thus obtained was dissolved in dichloroethane (12 g) and ammonium formate (2.1 g) were dissolved in metha ml). Triethylamine (1.44 ml) was added and the mixture was nol (30 ml). Catalyst (1 g) of 10% palladium/carbon was stirred under ice-cooling. A solution of triphenylmethyl added, and the mixture was stirred at 60° C. for 2 hours. The chloride (1.44 g) in dichloroethane (6 ml) was dropwise reaction mixture was filtered through Celite to remove added, and the mixture was stirred for 1 hour. The reaction catalyst and the filtrate was concentrated. The residue was mixture was extracted with chloroform. The extract was partitioned between chloroform and water. The organic layer 55 washed with an aqueous citric acid solution and dried over was washed with water, dried over magnesium sulfate, and magnesium sulfate. The solvent was evaporated, and the concentrated under reduced pressure to give tert-butyl residue was recrystallized from ethyl acetate to give 1.8g of 3-aminobenzoate. This compound was dissolved in tetrahy ethyl 1-(1-triphenylmethyltetrazol-5-yl)methylindole-2- drofuran (30 ml). NN'-Carbonyldiimidazole (1.05 g) was carboxylate. added, and the mixture was stirred at room temperature for mp. 142-144° C. 3 hours. Triethylamine (1.82 ml) and 3-aminomethyl-4-(3- Ethyl 1-(1-triphenylmethyltetrazol-5-yl)methylindole-2- (2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1.24) carboxylate (1.71 g) obtained was dissolved in dimethylfor triazole di-p-toluenesulfonate (4.82 g) were added to the mamide (15 ml). A 2N sodium hydroxide aqueous solution reaction mixture, and the mixture was further stirred at room (3.3 ml) was added, and the mixture was stirred. An aqueous temperature for 3 hours. The reaction mixture was concen 65 citric acid solution was added to the reaction mixture, and trated. The residue was partitioned between ethyl acetate and the mixture was extracted with ethyl acetate. The extract was water. The organic layer was washed with a 5% aqueous dried over magnesium sulfate. The solvent was evaporated, 5,760,032 95 96 and the residue was recrystallized from ethyl acetate to give dissolved in tetrahydrofuran (20 ml), and the reaction mix 1.53 g of 1-(1-triphenylmethyltetrazol-5-yl)methylindole-2- ture was kept at 60° C. for 1 hour to give carboxylic acid. 3-dimethylaminophenyl isocyanate. The reaction mixture mp. 210°-212° C. was cooled to 0° C. Triethylamine (4.2 ml) and 1-(1-Triphenylmethyltetrazol-5-yl)methylindole-2- 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- carboxylic acid (1.50 g) thus obtained and 3-aminomethyl yl)-5-methyl 12.4 triazole di-p-toluenesulfonate (7.42 g) 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1.2, were added, and the mixture was stirred for 2 hours. The 4triazole di-p-toluenesulfonate (2.23 g) were dissolved in reaction mixture was concentrated. The residue was parti dimethylformamide (45 ml). Triethylamine (1.68 ml) and tioned between ethyl acetate and water. The organic layer Bop reagent (1.33 g) were added under ice-cooling, and the O was washed with a saturated aqueous sodium hydrogencar mixture was stirred at room temperature. The reaction bonate solution and saturated brine, and dried over magne mixture was partitioned between water and ethyl acetate. sium sulfate. The solvent was evaporated. The obtained The organic layer was washed with an aqueous citric acid residue was purified by silica gel column chromatography solution, saturated brine, a saturated aqueous sodium hydro using a mixed solvent of ethyl acetate and methanol (10:1) gencarbonate solution and saturated brine, and dried over 15 as an eluent and by silica gel column chromatography using magnesium sulfate. The solvent was evaporated, and the a mixed solvent of chloroform and methanol (50:1) as an residue was purified by silica gel column chromatography eluent, and crystallized from ethyl acetate to give 140 mg of using a mixed solvent of ethyl acetate and methanol as an N-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl eluent to give 0.68 g of N-(4-(3-(2-chlorobenzoyl)-5- 1.2.4 triazol-3-yl)methyl)-N'-(3-dimethylaminophenyl) ethylthiophen-2-yl)-5-methyl(1,2,4-triazol-3-ylmethyl)-1- 20 (1-triphenylmethyltetrazol-5-yl)methylindole-2- mp. 179°-181° C. carboxamide. mp. 90°-105° C. EXAMPLE 293 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- N-((4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- methyl 1, 2, 4 triazol-3-yl methyl)-1-(1- 25 methyl(1.2.4 triazol-3-yl)methyl)-N'-(3- nitrophenyl)urea triphenylmethyltetrazol-5-yl)methylindole-2-carboxamide (4.07 g) was obtained in the same manner as in Example 23 (0.5 g) thus obtained was dissolved in tetrahydrofuran (10 using 3-Ditrophenyl isocyanate (1.64 g), 3-aminomethyl-4- ml). Conc. hydrochloric acid (2 ml) was added and the (3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 mixture was stirred at room temperature for 1 hour. The 30 triazole di-p-toluenesulfonate (7.42 g) and triethylamine reaction mixture was extracted with ethyl acetate, and the (2.8 ml). extract was dried over magnesium sulfate. The solvent was mp. 1579-159° C. evaporated, and the residue was crystallized from isopropyl alcohol to give 0.24 g of N-(4-(3-(2-chlorobenzoyl)-5- EXAMPLE 2.94 ethylthiophen-2-yl)-5-methyl(1,2,4-triazol-3-ylmethyl)-1- (1H-tetrazol-5-yl)methylindole-2-carboxamide. 35 2.3.9-Trimethyl-4-(4-chlorophenyl)-6H-thieno3.2-f 1.2.4 triazolo 4,3-a 1.4)diazepine (1.0 g) and mp. 238°-241° C. 10-camphorsulfonic acid (2.1 g) was dissolved in a mixed EXAMPLE 291 solvent (25 ml) of ethanol and water (9:1), and the mixture was refluxed for 3 hours. The reaction mixture was concen N-(3-(tert-Butoxycarbonylamino)phenyl)-N'-(4-(3-(2- trated under reduced pressure, and the obtained residue was chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) dissolved in dimethylformamide (10 ml). 2-Methoxyphenyl triazol-3-ylmethyl)urea (5.39 g) was obtained in the same isocyanate (0.40 ml) and triethylamine (1.47 ml) were manner as in Example 193 using 3-(N-tert added, and the mixture was stirred at room temperature for butoxycarbonylamino)aniline (4.94 g). N,N'- one day. The reaction mixture was partitioned between carbonyldiimidazole (4.04 g), 3-aminomethyl-4-(3-(2- 45 chloroform and water, The organic layer was washed with a chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) 10% aqueous citric acid solution and saturated brine, and triazole di-p-toluenesulfonate (17.62 g) and triethylamine dried over magnesium sulfate. The solvent was concentrated (8.31 ml). under reduced pressure. The obtained solid was subjected to m.p. 214-215° C. silica gel column chromatography using a mixed solvent of Then, this compound (595 mg) was dissolved in trifluo 50 ethyl acetate and methanol as an eluent, and N-((4-(3-(4- roacetic acid (6 ml), and the mixture was allowed to stand chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-5-methyl(1.24) at room temperature for one day. The reaction mixture was triazol-3-yl)methyl)-N'-(2-methoxyphenyl)urea (900 mg) concentrated. The residue was partitioned between ethyl was obtained from a fraction containing the objective com acetate and water. The organic layer was washed with a pound. saturated aqueous sodium hydrogencarbonate solution and 55 mp. 228°-230° C. saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the EXAMPLE 295 residue was crystallized from isopropanol and recrystallized 2.9-Dimethyl-4-phenyl-6H-thieno3.2-f 1.2.4 triazolo from ethanol to give 270 mg of N-(3-aminophenyl)-N'-(4- 4.3-a 14-diazepine (882 mg) and 10-camphorsulfonic (3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 acid (2.1 g) was dissolved in a mixed solvent (25 ml) of triazol-3-ylmethyl)urea. ethanol and water (9:1), and the mixture was refluxed for 3 mp. 1899-191° C. hours. The reaction mixture was concentrated under reduced EXAMPLE 292 pressure. The obtained residue was dissolved in dimethyl 65 formamide (10 ml). Indole-2-carbonyl chloride (538 mg) 3-Dimethylaminobenzoic acid (1.65 g), diphenylphos and triethylamine (1.4 ml) were added and the mixture was phoryl azide (2.16 ml) and triethylamine (1.4 ml) were stirred at room temperature for one day. The reaction mix 5,760,032 97 98 ture was partitioned between ethyl acetate and water. The EXAMPLE 300 organic layer was washed with a saturated aqueous sodium In the same manner as in Example 186, 1-(2- hydrogencarbonate solution and saturated brine, and dried ethoxycarbonylethyl)indole-2-carboxylic acid (3.22 g), over magnesium sulfate. The solvent was concentrated 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- under reduced pressure. The obtained solid was recrystal 5 yl)-5-methyl(1,24triazole di-p-toluenesulfonate (9.15 g). lized from a mixed solvent of ethyl acetate and methanol to triethylamine (6.9 ml) and 1-benzotriazolyloxytris give 0.61 g of N-(4-(3-benzoyl-5-methylthiophen-2-yl)-5- (dimethylamino)phosphonium hexafluorophosphate (Bop methyl 12.4 triazol-3-ylmethyl)indole-2-carboxamide. reagent, 5.44 g) were reacted, and the reaction mixture was mp. 231-233° C. purified by silica gel column chromatography using a mixed 10 solvent of ethyl acetate and methanol (10:1) as an eluent, EXAMPLE 296 followed by crystallization from acetone to give 5.07 g of 3-Methylindole-2-carboxylic acid (0.5 g) and ethyl 3-((2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)- 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- 5-methyl(1,2,4-triazol-3-yl)methylcarbamoyl)indol-1-yl) yl)-5-methyl 12,4-triazole di-p-toluenesulfonate (2.1 g) propionate. was dissolved in DMF (42 ml). Triethylamine (1.6 ml) and 15 mp. 99°-101° C. Bop reagent (1.32 g) were added under ice-cooling, and the mixture was stirred for 6 hours. Water was added, and the EXAMPLE 301 mixture was extracted with ethyl acetate. The extract was Benzyl indole-2-carboxylate (50.2 g) was dissolved in washed with an aqueous citric acid solution, saturated brine, DMF (500 ml). Sodium hydride (60% oil, 1.8 g) was added a saturated aqueous sodium hydrogencarbonate solution and under ice-cooling and the mixture was stirred for 30 min saturated brine, and dried over magnesium sulfate. The utes. Ethyl 4-bromobutanoate (30.1 ml) was further added solvent was evaporated, and the residue was purified by and the mixture was stirred for 4 hours. The reaction mixture silica gel column chromatography using a mixed solvent of was concentrated under reduced pressure. The obtained ethyl acetate and methanol as an eluent and recrystallized residue was partitioned between ethyl acetate and water. The from a mixed solvent of ethyl acetate and hexane to give 25 organic layer was washed with saturated brine and dried 0.22 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)- over magnesium sulfate. The solvent was evaporated, and 5-methyl(1.2.4 triazol-3-yl-methyl)-3-methyl-1H-indole-2- the residue was crystallized from ethyl acetate to give a carboxamide. crude product of benzyl 1-(3-ethoxy-carbonylbutyl)indole mp. 143°-147 C. 2-carboxylate. This product was dissolved in ethanol (350 30 ml) and hydrogenated by blowing a hydrogen gas in the EXAMPLE 297 presence of 10% palladium/carbon (25 g). The reaction mixture was filtered through Celite, and the filtrate was N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- concentrated under reduced pressure. The residue was crys methyl(1.24triazol-3-ylmethyl)indole-2-carboxamide (1.0 tallized from isopropyl alcohol to give 39.1 g of 1-(3- g. Example 14) was dissolved in acetic acid (12 ml). 35 ethoxycarbonylpropyl)indole-2-carboxylic acid. Bromine (0.1 ml) dissolved in acetic acid (1 ml) was dropwise added under water-cooling, and the mixture was In the same manner as in Example 186, the reaction was stirred for 1 hour. The solvent was evaporated, and an carried out using 1-(3-ethoxycarbonylpropyl)indole-2- aqueous sodium thiosulfate solution was added. The mixture carboxylic acid (0.52 g) obtained, 3-aminomethyl-4-(3-(2- was extracted with chloroform. The extract was washed with chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4) saturated brine, a saturated aqueous sodium hydrogencar triazole di-p-toluenesulfonate (1.4 g), triethylamine (1.06 bonate solution and saturated brine, and dried over magne ml) and 1-benzotriazolyloxytris(dimethylamino) sium sulfate. The solvent was evaporated, and the residue phosphonium hexafluorophosphate (Bop reagent, 0.84 g). was recrystallized from methanol to give 0.36 g of N-(4-(3- Purification of the reaction mixture by silica gel column (2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12,4 45 chromatography using a mixed solvent of ethyl acetate and triazol-3-ylmethyl)-3-bromoindole-2-carboxamide. methanol (10:1) as an eluent and crystallization from a mixed solvent of hexane-ethyl acetate gave 0.56 g of ethyl mp. 2009-202° C. 4-((2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- EXAMPLE 298 methyl 1.2.4 triazol-3-yl)methylcarbamoyl)indol-1-yl) 50 butanoate. N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- mp. 105°-106° C. methyl 12.4 triazol-3-ylmethyl)-3-chloroindole-2- carboxamide is obtained in the same manner as in Example EXAMPLE 302 186 using 3-chloroindole-2-carboxylic acid synthesized Ethyl 4-((2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- according to Nippon Kagaku Zasshi, Vol. 81, No. 9, 1431 55 yl)-5-methyl 12.4 triazol-3-yl)methylcarbamoyl)indol-1- (1960). 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- yl)butanoate (0.54 g) was dissolved in methanol (10 ml). A ethylthiophen-2-yl)-5-methyl 1,2,4-triazole di-p- 2N sodium hydroxide aqueous solution (0.87ml) was added toluenesulfonate, dimethylformamide, triethylamine and and the mixture was allowed to stand at room temperature Bop reagent. for one day. Treatment in the same manner as in Example 19 gave 0.35 g of 4-((2-(4-(3-(2-chlorobenzoyl)-5- EXAMPLE 299 ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-yl) N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- methylcarbamoyl)indol-1-yl)butanoic acid. methyl 12.4 triazol-3-ylmethyl)-indole-2-carboxamide is mp. 176°-177° C. dissolved in dichloroethane, and reacted with 1-fluoro-2,6- dichloropyridinium trifiate to give N-(4-(3-(2- 65 EXAMPLE 303 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) Benzylindole-2-carboxylate (10g) was dissolved in DMF triazol-3-ylmethyl)-3-fluoroindole-2-carboxamide. (100 ml). Sodium hydride (60% oil, 1.8 g) was added under 5,760,032 99 100 ice-cooling, and the mixture was stirred for 30 minutes. hexanoic acid is obtained in the same manner as in Example Ethyl 5-bromopentanoate (6.7ml) was further added and the 271 using ethyl 6-(2-((4-(3-(2-chlorobenzoyl)-5- mixture was stirred for 6 hours. Water was added to the ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-yl) reaction mixture, and the mixture was extracted with ethyl methylcarbamoyl)indol-1-yl)hexanoate obtained, methanol acetate. The mixture was washed with saturated brine and and a 2N sodium hydroxide aqueous solution. dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chroma EXAMPLE 307 tography using a mixed solvent of ethyl acetate and hexane Benzyl 5-fluoroindole-2-carboxylate (9.4 g) was dis as an eluent to give 12.44 g of benzyl 1-(4- solved in DMF (94 ml). Potassium carbonate (9.7 g) and ethoxycarbonylbutyl)indole-2-carboxylate. bromoethyl acetate (4.0 ml) were added and the mixture was Benzyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate stirred for 5 hours. The reaction mixture was partitioned (12.44 g) was dissolved in ethanol (120 ml). The mixture between ethyl acetate and water. The organic layer was was subjected to catalytic reduction by blowing a hydrogen washed with saturated brine and dried over magnesium gas in the presence of 10% palladium/carbon. The reaction sulfate. The solvent was evaporated, and the residue was mixture was filtered through Celite to remove catalyst. The 15 recrystallized from isopropyl alcohol to give 9.59 g of solvent was evaporated, and the residue was purified by benzyl 1-ethoxycarbonylmethyl-5-fluoroindole-2- silica gel column chromatography using a mixed solvent of carboxylate. ethyl acetate and hexane as an eluent to give 2.19 g of 1-(4-ethoxycarbonylbutyl)indole-2-carboxylic acid. mp. 75°-76° C. 1-(4-Ethoxycarbonylbutyl)indole-2-carboxylic acid (2.19 Benzyl 1-ethoxycarbonylmethyl-5-fluoroindole-2- g) thus obtained and 3-aminomethyl-4-(3-(2- carboxylate (8.53 g) thus obtained was dissolved in ethanol chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1.2.4 triaz (85 ml). The solution was subjected to catalytic reduction by ole di-p-toluenesulfonate (5.62 g) were dissolved in DMF blowing a hydrogen gas in the presence of 5% palladium/ (100 ml). Triethylamine (4.2 ml) and Bop reagent (3.35 g) carbon (8.5 g). After filtration through Celite, the solvent 25 was evaporated, and the obtained solid was recrystallized were added under ice-cooling, and the mixture was stirred at form isopropyl ether to give 2.96 g of room temperature for one day. Water was added, and the 1-ethoxycarbonylmethyl-5-fluoroindole-2-carboxylic acid. mixture was extracted with ethyl acetate. The extract was washed with an aqueous citric acid solution, saturated brine, 1-Ethoxycarbonylmethyl-5-fluoroindole-2-carboxylic a saturated aqueous sodium hydrogencarbonate solution and acid (1.0 g) obtained and 3-aminomethyl-4-(3-(2- saturated brine and dried over magnesium sulfate. The chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 solvent was evaporated, and the residue was purified by triazole di-p-toluenesulfonate (2.8 g) were dissolved in silica gel column chromatography using a mixed solvent of DMF (56ml). Triethylamine (2.1 ml) and Bop reagent (1.8 ethyl acetate and methanol as an eluent and recrystallized g) were added under ice-cooling, and the mixture was stirred from a mixed solvent of ethyl acetate and hexane to give at room temperature for 4 hours. Water was added, and the 0.295 g of ethyl 5-(2-((4-(3-(2-chlorobenzoyl)-5- mixture was extracted with ethyl acetate. The organic layer ethylthiophen-2-yl)-5-methyl(1,2,4-triazol-3-yl) was washed with an aqueous citric acid solution, saturated methylcarbamoyl)indol-1-yl)pentanoate 1/2 hydrate. brine, a saturated aqueous sodium hydrogencarbonate solu tion and saturated brine and dried over magnesium sulfate. mp. 85-87 C. - The solvent was evaporated, and the residue was crystallized EXAMPLE 304 from ethyl acetate to give 1.97 g of ethyl (2-(4-(3-(2- 5-(2-((4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4) methyl 1.2.4 triazol-3-yl)methylcarbamoyl)indol-1-yl) triazol-3-ylmethyl)carbamoyl-5-fluoroindol-1-yl)acetate. pentanoic acid (0.10 g) was obtained in the same manner as mp. 125°-127° C. in Example 271 using ethyl 5-(2-((4-(3-(2-chlorobenzoyl)- 5-ethylthiophen-2-yl)-5-methyl(1,2,4-triazol-3-yl) 5 EXAMPLE 308 methylcarbamoyl)indol-1-yl)pentanoate (0.25 g) thus (2-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- obtained, methanol (3 ml) and a 2N sodium hydroxide methyl 1.2.4 triazol-3-ylmethyl)carbamoyl-5-fluoroindol aqueous solution (0.4 ml). 1-yl)acetic acid (0.24 g) was obtained in the same manner as NMR (270 MHz, CDC1):1.33(3Hit.J=7.5 Hz), 149-153 in Example 271 using ethyl (2-(4-(3-(2-chlorobenzoyl)-5- (2Him), 1.77-1.82(2Him), 2.29(2H,t), 2.34(3H.s), 2.82(2H, 50 ethylthiophen-2-yl)-5-methyl(1.2.4 triazol-3-ylmethyl) qJ=7.5 Hz). 4.40-4.55(2Him), 4.53-4.82(2Him), 6.76(1H, carbamoyl-5-fluoroindol-1-yl)acetate (1.64 g), methanol (16 s), 6.93-7.61(10Hm) ml) and a 2N sodium hydroxide aqueous solution (2.7 ml). EXAMPLE 305 mp. 174°-175° C. 1-(5-Ethoxycarbonylpentyl)indole-2-carboxylic acid was 55 EXAMPLE 309 prepared using benzyl indole-2-carboxylate, DMF, sodium hydride (60% in oil) and ethyl 5-bromohexanoate, and ethyl 1-(4-Ethoxycarbonylbutyl)indole-2-carboxylic acid was 6-(2-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- obtained in the same manner as in Example 301 using benzyl methyl(1,24triazol-3-yl)methylcarbamoyl)indol-1-yl) 5-fluoroindole-2-carboxylate (5.0 g), DMF (50 ml), sodium hexanoate was synthesized in the same manner as in hydride (60% oil, 0.82 g) and ethyl bromobutaneacetate (2.8 Example 186 using 3-aminomethyl-4-(3-(2-chlorobenzoyl) ml). Reaction with 3-aminomethyl-4-(3-(2-chlorobenzoyl)- -5-ethylthiophen-2-yl)-5-methyl 1,2,4-triazole di-p- 5-ethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- toluenesulfonate, triethylamine and Bop reagent. toluenesulfonate (4.9 g), Bop reagent (2.92 g) and triethy lamine (3.7 ml) gave 1.84 g of ethyl 4-(2-(4-(3-(2- EXAMPLE 306 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4) 6-(2-((4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- triazol-3-ylmethyl)carbamoyl-5-fluoroindol-1-yl)butanoate. methyl 12,4triazol-3-yl)methylcarbamoyl)indol-1-yl) mp. 127°-128° C. 5,760,032 101 102 EXAMPLE 310 reaction mixture was cooled to room temperature. Sodium hydrogencarbonate was added to make the reaction mixture 4-(2-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- alkaline. Chloroform and indole-2-carbonyl chloride (0.33 methyl(1,2,4-triazol-3-ylmethyl)carbamoyl-5-fluoroindol g) were added, and the mixture was stirred for 0.5 hour. The 1-yl)butanoic acid (0.79g) was obtained in the same manner organic layer was washed with saturated brine and dried as in Example 271 using ethyl 4-(2-(4-(3-(2-chlorobenzoyl) over magnesium sulfate. The solvent was concentrated -5-ethylthiophen-2-yl)-5-methyl 12.4 triazol-3-ylmethyl) under reduced pressure, and the obtained residue was crys carbamoyl-5-fluoroindol-1-yl)butanoate (1.6 g), methanol tallized from ethyl acetate to give 0.2 g of N-(3-chloro-4- (16 ml) and a 2N sodium hydroxide aqueous solution (2.5 (3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) 1.2.4 triazol-5- ml). 10 ylmethyl)indole-2-carboxamide. mp. 1779-1799 C. mp. 254°-256° C. EXAMPLE 311 EXAMPLE 316 Ethyl (3-bromo-2-(4-(3-(2-chlorobenzoyl)-5- N-(3-Chloro-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-ylmethyl) 15 yl) 1.2.4 triazol-5-ylmethyl)-3,4-dichlorobenzamide is carbamoyl-indol-1-yl)acetate (1.02 g) was obtained in the obtained in the same manner as in Example 315 using same manner as in Example 297 using ethyl 2-(4-(3-(2- 9-chloro-4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2. chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) 4triazolo 4.3-a) (14)diazepine and 3,4-dichlorobenzoyl triazol-3-ylmethylcarbamoyl)indole-1-acetate (1.76 g. chloride. Example 18), acetic acid (23 ml) and bromine (0.15 ml). 20 mp. 56°-58° C. EXAMPLE 317 EXAMPLE 312 Ethyl 2-(5-chloro-4-(3-(2-chlorobenzoyl)-5- ethylthiophen-2-yl) 12.4)triazol-3-ylmethylcarbamoyl) (3-Bromo-2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- 25 indole-1-acetate is obtained in the same manner as in yl)-5-methyl(1,2,4-triazol-3-ylmethyl)carbamoyl-indol-1- Example 315 from 9-chloro-4-(2-chlorophenyl)-2-ethyl-6H yl)acetic acid is obtained in the same manner as in Example thieno3.2-f 1.2.4 triazolo.4.3-a 1,4-diazepine and 271 using ethyl (3-bromo-2-(4-(3-(2-chlorobenzoyl)-5- 1-(ethoxycarbonylmethyl)indole-2-carbonyl chloride. ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-ylmethyl) carbamoyl-indol-1-yl)acetate obtained, methanol and a 2N 30 EXAMPLE 318 sodium hydroxide aqueous solution. Ethyl 2-(5-chloro-4-(3-(2-chlorobenzoyl)-5- EXAMPLE 313 ethylthiophen-2-yl) (1,2,4-triazol-3-ylmethylcarbamoyl) indole-1-acetate is subjected to alkali hydrolysis to give Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- 2-(5-chloro-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) methyl 12.4 triazol-3-ylmethylcarbamoyl)indole-1-acetate 35 124triazol-3-ylmethylcarbamoyl)indole-1-acetic acid. is dissolved in dichloroethane, and reacted with 1-fluoro-2, 6-dichloropyridiniumtriflate to give ethyl 2-(4-(3-(2- EXAMPLE 319 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 triazol-3-ylmethylcarbamoyl)-3-fluoroindole-1-acetate. 1-Ethoxycarbonylmethyl-3-methylindole-2-carboxylic acid is obtained in the same manner as in Example 307 using EXAMPLE 314 benzyl 3-methylindole-2-carboxylate, DMF, potassium car bonate and bromoethyl acetate, and reacted with Bop Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- reagent to give ethyl (2-(4-(3-(2-chlorobenzoyl)-5- methyl(1.2.4 triazol-3-ylmethylcarbamoyl)-3-fluoroindole ethylthiophen-2-yl)-5-methyl 12.4 triazol-3-ylmethyl) 1-acetate is subjected to alkali hydrolysis to give 2-(4-(3- 45 carbamoyl-3-methylindol-1-yl)acetate. (2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(12.4) triazol-3-ylmethylcarbamoyl)-3-fluoroindole-1-acetic acid. EXAMPLE 320 Production Example 13 (2-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- 50 methyl(1.24triazol-3-ylmethyl)carbamoyl-3-methylindol 4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4) 1-yl)acetic acid is obtained in the same manner as in triazolo 4.3- a 1,4 diazepine (10.0 g) and Example 271 using ethyl (2-(4-(3-(2-chlorobenzoyl)-5- N-chlorosuccinimide (4.55 g) were dissolved in dimethyl ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-ylmethyl) formamide (50 ml), and the mixture was stirred at room carbamoyl-3-methylindol-1-yl)acetate thus obtained, temperature overnight. Ethyl acetate and water were added methanol and a 2N sodium hydroxide aqueous solution. thereto. The organic layer was washed with water and dried 55 over magnesium sulfate. The solvent was concentrated EXAMPLE 321 under reduced pressure, and the obtained residue was puri 1-(3-Ethoxycarbonylpropyl)-3-methylindole-2- fied by silica gel column chromatography to give 1.8g of carboxylic acid was obtained in the same manner as in 9-chloro-4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2, Example 303 using benzyl 3-methylindole-2-carboxylate, 4triazolo4.3-a 14-diazepine. and reacted in the same manner as in Example 186 using mp. 133°-135° C. 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- yl)-5-methyl 12.4 triazole di-p-toluenesulfonate (2.43 g). EXAMPLE 315 triethylamine (1.8 ml) and 1-benzotriazolyloxytris 9-Chloro-4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 65 (dimethylamino)phosphonium hexafluorophosphate (Bop 1.2.4 triazolo4.3-a 1,4-diazepine (0.5 g) was stirred with reagent, 1.45 g). Purification by silica gel column chroma 2M hydrochloric acid (12.5 ml) at 60° C. for 2.5 hours. The tography using a mixed solvent of ethyl acetate and metha 5,760,032 103 104 nol (10:1) as an eluent and crystallization from a mixed propionate (1.0 g) was subjected to alkali hydrolysis to give solvent of hexane-ethyl acetate gave 1.07 g of ethyl 4-(2- 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl (4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1, 1.2.4 triazol-3-yl)-3-((indol-2-yl)carbonylamino)propionic 2.4 triazol-3-ylmethyl)carbamoyl-3-methylindol-1-yl) acid (0.81 g). butanoate 1/2 hydrate. NMR (270 MHz, DMSO-d):0.73-1.25(3H), 2.19-2.21 m.p. 96°-98° C. (3H), 2.45-3.42(4H). 5.53-5.80(1H), 6.57-7.67(1OH), EXAMPLE 322 8.79-8.87(1H), 11.48(1H), 12.34(1H) 4-(2-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- Production Example 14 methyl 12,4-triazol-3-ylmethyl)carbamoyl-3-methylindol 10 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno3.2-f 1-yl)butanoic acid (0.37 g) was obtained in the same manner (1.2.4 triazolo 4.3-a 14-diazepine (10.0 g) and 60% as in Example 271 using ethyl 4-(2-(4-(3-(2-chlorobenzoyl)- sodiumhydride (2.0 g) were added to diethyl carbonate (150 5-ethylthiophen-2-yl)-5-methyl 12,4-triazol-3-ylmethyl) ml), and the mixture was refluxed under heating under a carbamoyl-3-methylindol-1-yl)butanoate (0.80 g) thus nitrogen atmosphere for 2 hours. The reaction mixture was obtained, methanol (8 m) and a 2N sodium hydroxide 15 cooled to 50° C. Ethyl acrylate (5.37 ml) was added and the aqueous solution (1.2 ml). mixture was further stirred for 3 hours. The reaction mixture NMR (270 MHz, CDC1):1.33(3H,t.J=7.4 Hz), 2.04-2.23 was added to water. 1M Hydrochloric acid was added with (4H.m), 2.35(3H,s), 2.48(3H.s), 2.85(2H.qJ=7.4 Hz), vigorous stirring to adjust the aqueous solution to pH4. The 4.34–4.51(2H.m), 4.56.4.87(2H.m). 6.79(1Hs), 7.08-7.58 solution was extracted with ethyl acetate. The extract was (10H.m) washed with a saturated aqueous sodium hydrogencarbonate EXAMPLE 323 solution and brine. and dried over magnesium sulfate. The residue was purified by silica gel column chromatography Ethyl 2-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno (developing solventiethyl acetate-hexane) to give 3.2 g of (32-f 1.24triazolo43-a 14-diazepin-6-yl)acetate (1.0 ethyl 4-(2-chlorophenyl)-6-(2-ethoxycarbonylethyl)-2- g) synthesized by a known method such as WO94706802 25 ethyl-9-methyl-6H-thieno3,2-f 1,2,4-triazolo43-a 1.4) was added to 2M hydrochloric acid (24 ml), and the mixture diazepine-6-carboxylate. was stirred at 60° C. for 0.5 hour. The reaction mixture was cooled to 0° C. A saturated aqueous sodium hydrogencar Ethyl 4-(2-chlorophenyl)-6-(2-ethoxycarbonylethyl)-2- bonate solution, chloroform and 3.4-dichlorobenzoyl chlo ethyl-9-methyl-6H-thieno3.2-f 12.4 triazolo43-a 1.4) ride (0.53 g) were added and the mixture was stirred for 1 30 diazepine-6-carboxylate (23 g) was dissolved in ethanol (92 hour. The organic layer was taken out and dried over ml), A4M sodium hydroxide aqueous solution (92 ml) was magnesium sulfate. The residue was purified by silica gel added and the mixture was stirred at 60° C. for 6 hours. 2M column chromatography (developing solventiethyl acetate Hydrochloric acid was added to adjust the aqueous solution hexane) and crystallized from diisopropyl ether to give 0.06 to pH 2. The solution was extracted with ethyl acetate. The g of ethyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)- 35 extract was dried over magnesium sulfate, and concentrated. 5-methyl 12.4 triazol-3-yl)-3-(3,4-dichlorobenzoylamino) The obtained crystals were taken out, and washed with propionate. diisopropyl ether to give 13.5g of 3-(4-(2-chlorophenyl)-2- ethyl-9-methyl-6H-thieno3.2-f 12.4 triazolo43-a 1.4) NMR (270 MHz, DMSO-d):0.85-127(6H), 2.18-222 diazepin-6-yl)propionic acid. (3H), 2.56-3.65(4H), 3.93-4.09(2H). 5.54-5.74(1H), 3-(4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno3, 6.56-7.99(8H), 9.07-9.12(1H) 2-f 1.2.4 triazolol4,3-a 14-diazepin-6-yl)propionic acid EXAMPLE 324 (13.5 g) was dissolved in dimethylformamide (140 ml). Ethyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- Potassium carbonate (9.1 g) and iodoethane (2.9 ml) were methyl 1.2.4 triazol-3-yl)-3-(3,4-dichlorobenzoylamino) added, and the mixture was stirred for 4 hours. Ethyl acetate propionate (0.55g) was subjected to alkalihydrolysis to give 45 and water were added thereto. The organic layer was taken 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl out, washed with brine and dried over magnesium sulfate. 1,2,4-triazol-3-yl)-3-(3,4-dichlorobenzoylamino)propionic The solvent was evaporated, and the residue was crystallized acid (0.23 g). from diisopropyl ether to give 11.2 g of ethyl 3-(4-(2- NMR (270 MHz, DMSO-d):0.88-1.26(3H), 2.17-2.21 chlorophenyl)-2-ethyl-9-methyl-6H-thieno3.2-f 1.2.4 (3H), 2.57-3.35(4H), 5.48-5.70(1H), 6.65-8.00(8H). 50 triazolo43-a 1.4ldiazepin-6-yl)propionate. 9,049.10(1H), 12.34(1H) EXAMPLE 327 EXAMPLE 325 Ethyl 3-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno Ethyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- 3.2-f 1.2.4 triazolo43-a 14-diazepin-6-yl)propionate methyl 1.2.4 triazol-3-yl)-3-((indol-2-yl)carbonylamino) 55 (4.0 g) was added to 2M hydrochloric acid (100 ml), and the propionate (1.63 g) was obtained in the same manner as in mixture was stirred at 60° C. for 1 hour. The reaction Example 323 using ethyl 2-(4-(2-chlorophenyl)-2-ethyl-9- mixture was cooled to 0 C. A saturated aqueous sodium methyl-6H-thieno 3.2-f 1.2.4 triazolo 4.3-a 1.4 hydrogencarbonate solution, chloroform and 3,4- diazepin-6-yl)acetate (6.9 g) and indole-2-carbonyl chloride dichlorobenzoyl chloride (2.1 g) were added, and the mix (3.18 g). ture was stirred for 0.5 hour. The organic layer was taken NMR (270 MHz, DMSO-d):0.68-1.26(6H). 2.18-222 out, dried over magnesium sulfate and concentrated under (3H), 2.42-3.45(4H), 3.93-4.11(2H), 5.59-5.83(1H), reduced pressure. The obtained residue was purified by silica 6.53-7.69(10H), 8.81-8.89(1H), 11.46-11.48(1H) gel column chromatography (developing solvent: ethyl acetate) and crystallized from a mixed solvent of ethyl EXAMPLE 326 65 acetate-diisopropyl ether to give 0.56 g of ethyl 4-(4-(3-(2- Ethyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1,2,4- methyl 1.2.4 triazol-3-yl)-3-((indol-2-yl)carbonylamino) triazol-3-yl)-4-(3,4-dichlorobenzoylamino)butanoate. 5,760,032 105 106 NMR (270 MHz, DMSO-d):0.66-1.24(6H), 2.17-2.23 was obtained in the same manner as in Example 186 using (3H), 2.32-2.87(6H), 3.89-4.07(2H), 5.17-5.38(1H). indole-1-acetic acid (1.0 g), 3-aminomethyl-4-(3-(2- 6.63-8.02(8H), 8.93-8.99(1H) chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 triazole di-p-toluenesulfonate (3.3 g), triethylamine (2.7 ml) EXAMPLE 328 and 1-benzotriazolyloxytris(dimethylamino)phosphonium Ethyl 4-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- hexafluorophosphate (Bop reagent, 2.5 g). methyl 124triazol-3-yl)-4-(3,4-dichlorobenzoylamino) mp. 1769-177° C. butanoate (0.47 g) was subjected to alkali hydrolysis to give 4-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl EXAMPLE 332 1,2,4-triazol-3-yl)-4-(3,4-dichlorobenzoylamino)butanoic 10 acid (0.17 g). Ethyl 1-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)- NMR (270 MHz. DMSO-d):0.88-1.24(3H), 2.09-2.86 5-methyl 12.4 triazol-3-yl)methylcarbamoylmethyl) (9H), 5.14-5.34(1H), 6.63-8.02(8H), 8.91-8.98(1H), 12.08 indole-2-carboxylate (16.45 g) was obtained in the same (1H) manner as in Example 186 using 2-ethoxycarbonyl-indole 15 1-acetic acid (9.0 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl) EXAMPLE 329 -5-ethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- Ethyl 4-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- toluenesulfonate (27.37 g), triethylamine (20.7 ml) and methyl 1,2,4-triazol-3-yl)-4-((1H-indol-2-yl) 1-benzotriazolyloxytris(dimethylamino)phosphonium carbonylamino)butanoate (0.12 g) was obtained in the same hexafluorophosphate (Bop reagent, 17.94 g). manner as in Example 327 from ethyl 3-(4-(2- 20 mp. 176°-177° C. chlorophenyl)-2-ethyl-9-methyl-6H-thieno3.2-f 1.2.4) triazolotA3-a 14-diazepin-6-yl)propionate (4.0 g) and EXAMPLE 333 indole-2-carbonyl chloride (1.8 g). Ethyl 1-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)- NMR (270 MHz, DMSO-d):0.71-123(6H), 2.17-222 5-methyl(1.2.4 triazol-3-yl)methylcarbamoylmethyl) (3H), 2.26-3.57(6H), 3.96-4.07(2H), 5.21-5.45(1H), 25 indole-3-carboxylate (250 mg) was obtained in the same 6.58-7.63(1OH), 8.65-8.78(1H), 11.46(1H) manner as in Example 186 using 3-ethoxycarbonyl-indole 1-acetic acid (1.22 g), 3-aminomethyl-4-(3-(2- EXAMPLE 330 chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1,2,4) Ethyl 4-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- triazole di-p-toluenesulfonate (3.71 g), triethylamine (2.8 methyl(1,24triazol-3-yl)-4-((indol-2-yl)carbonylamino) 30 ml), 1-benzotriazolyloxytris(dimethylamino)phosphonium butanoate (0.21 g) was subjected to alkali hydrolysis to give hexafluorophosphate (Bop reagent, 2.43 g). 4-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-yl)-4-((indol-2-yl)carbonylamino)butanoic mp. 182°-183° C. acid (0.11 g). EXAMPLE 334 35 NMR (270 MHz, DMSO-d):0.73-1.23(3H), 2.10-2.85 tert-Butyl 1-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- (9H), 5.18-5.40(1H), 6.58-7.63(10H), 8.63-8.77(1H). yl)-5-methyl 12.4 triazol-3-yl)methylcarbamoylmethyl) 11.45(1H), 12.08(1H) indole-3-carboxylate (2.86 g) was obtained in the same Production Example 15 manner as in Example 186 using 3-tert-butoxycarbonyl Ethyl indole-2-carboxylate (22 g) was dissolved in dim indole-1-acetic acid (2.75 g), 3-aminomethyl-4-(3-(2- ethylformamide (150 ml), and sodium hydride (including chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) 60% oil. 5.12 g) was gradually added with stirring. Then, triazole di-p-toluenesulfonate (7.42 g), triethylamine (7.0 benzyl bromoacetate (19.2 ml) was added, and the mixture ml) and 1-benzotriazolyloxytris(dimethylamino) was stirred for 3 hours. The reaction mixture was partitioned phosphonium hexafluorophosphate (Bop reagent, 4.64 g). between ethyl acetate and water. The organic layer was 45 mp. 129°-130° C. washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pres EXAMPLE 335 sure. The residue thus obtained as a solid was subjected to tert-Butyl 1-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- silica gel column chromatography and eluted with a mixed yl)-5-methyl 1.2.4 triazol-3-yl)methylcarbamoylmethyl) solvent of ethyl acetate and hexane to give benzyl indole-3-carboxylate (500mg) was dissolved in formic acid 2-ethoxycarbonyl-indole-1-acetate (28.9 g) as an oil. This (5 ml), and the solution was allowed to stand for one day. compound (32.5 g) was dissolved in ethanol (350 ml), and The reaction mixture was concentrated, and the obtained hydrogenated in the presence of palladium/carbon (10%) residue was crystallized from ethyl acetate to give 184 mg catalyst at 1 atm. The catalyst was filtered off, and the of 1-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- solvent was concentrated under reduced pressure. The 55 methyl(1,2,4-triazol-3-yl)methylcarbamoylmethyl)indole obtained residue was crystallized from isopropyl ether to give 10.22 g of 2-ethoxycarbonyl-indole-1-acetic acid. 3-carboxylic acid. In the same manner as in the above, 3-ethoxycarbonyl m.p. 253° C. (dec.) indole-1-acetic acid can be prepared using ethyl indole-3- carboxylate; 3-tert-butoxycarbonyl-indole-1-acetic acid can EXAMPLE 336 be prepared using tert-butyl indole-3-carboxylate; and Methyl 1-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) 3-methoxycarbonylmethyl-indole-1-acetic acid can be pre -5-methyl 1.2.4 triazol-3-yl)methylcarbamoylmethyl) pared using methyl indole-3-acetate. indole-3-acetate (0.44 g) was obtained in the same manner as in Example 186 using 3-methoxycarbonylmethyl-indole EXAMPLE 331 65 1-acetic acid (562 mg), 3-aminomethyl-4-(3-(2- N-((4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1,2,4) methyl(1,2,4-triazol-3-yl)methyl)indole-1-acetamide (1.5 g) triazole di-p-toluenesulfonate (1.69 g), triethylamine (1.28 5,760,032 107 108 ml) and 1-benzotriazolyloxytris(dimethylamino) hexafluorophosphate (Bop reagent, 4.42 g), and the obtained phosphonium hexafluorophosphate (Bop reagent, 1.06 g). product was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as an mp. 143-145° C. eluent to give 0.90 g of trans-N-(4-(3-(2-chlorobenzoyl)-5- ethylthiophen-2-yl)-5-methyl(1.2.4 triazol-3-ylmethyl)-3- EXAMPLE 337 (2-hydroxyphenyl)propenamide. NMR (270 MHz, CDC1) Methyl 1-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- :1.17(3H.t.J-7.6 Hz), 2.21(3H,s), 2.78(2H.q. J=7.6 Hz), yl)-5-methyl 1,2,4-triazol-3-yl)methylcarbamoylmethyl)- 4.33(1H.dd.J-43 Hz, 15.5 Hz), 4.51 (1H.dd.J=6.3 Hz, 15.5 indole-3-acetate is subjected to hydrolysis in the same Hz). 6.60(1H.d.J-16.8 Hz), 6.75-6.90(3H), 7.18(1Hm), manner as in Example 19 to give 1-((4-(3-(2- 7.35-7.65(6H), 8.52(1H,m), 10.01(1Hs) chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl(1,2,4)- O triazol-3-yl)methylcarbamoylmethyl)indole-3-acetic acid. EXAMPLE 342 Reaction was carried out in the same manner as in EXAMPLE 338 Example 186 using trans-3-(2-nitrophenyl)propenoic acid (1.93 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- Crude crystals of 2-amino-4-chloro-N-(4-(3-(2- 5 ethylthiophen-2-yl)-5-methyl ( 1.2.4 triazole di-p- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) toluenesulfonate (7.42 g), triethylamine (5.6 ml) and triazol-3-ylmethyl)benzamide (3.7 g) were obtained in the 1-benzotriazolyloxytris(dimethylamino)phosphonium same manner as in Example 186 using 2-amino-4- hexafluorophosphate (Bop reagent, 4.42 g), and the obtained chlorobenzoic acid (1.72 g), 3-aminomethyl-4-(3-(2- crude crystals were recrystallized from ethyl acetate to give chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 3.65 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen triazole di-p-toluenesulfonate (7.42 g), triethylamine (5.6 2-yl)-5-methyl(1,2,4-triazol-3-ylmethyl)-3-(2-nitrophenyl) ml) and 1-benzotriazolyloxytris(dimethylamino) propenamide. phosphonium hexafluorophosphate (Bop reagent, 4.42 g). The crystals were recrystallized from ethyl acetate to give mp. 180°-182° C. 1.83 g of the objective compound. 25 EXAMPLE 343 m.p. 211-213° C. Ammonium chloride (118 mg) and iron powder (1.0 g) were dissolved in a mixed solvent of ethanol (15 ml) and EXAMPLE 339 water (5 ml). trans-N-(4-(3-(2-Chlorobenzoyl)-5- ethylthiophen-2-yl)-5-methyl(1,2,4-triazol-3-ylmethyl)-3- 3-Amino-4-chloro-N-(4-(3-(2-chlorobenzoyl)-5- (2-nitrophenyl)propenamide (1.07 g) was carefully added ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-ylmethyl) under reflux to the reaction mixture, and the mixture was benzamide (1.81 g) was obtained in the same manner as in refluxed for 1 hour. The reaction mixture was filtered Example 186 using 3-amino-4-chlorobenzoic acid (1.72 g), through Celite, and the filtrate was concentrated. The residue 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2- was partitioned between ethyl acetate and water. The organic yl)-5-methyl 124triazole di-p-toluenesulfonate (7.42 g), 35 layer was washed with a saturated aqueous sodium hydro triethylamine (5.6 ml) and 1-benzotriazolyloxytris gencarbonate solution and saturated brine, and dried over (dimethylamino)phosphonium hexafluorophosphate (Bop magnesium sulfate. The solvent was concentrated under reagent, 4.64 g). reduced pressure. The obtained solid was recrystallized from mp. 231-233° C. ethyl acetate to give 0.60 g of trans-N-(4-(3-(2- chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4 EXAMPLE 340 triazol-3-ylmethyl)-3-(2-aminophenyl)propenamide. 4-Amino-3-chloro-N-(4-(3-(2-chlorobenzoyl)-5- mp. 141-143° C. ethylthiophen-2-yl)-5-methyl 1.2.4 triazol-3-ylmethyl) EXAMPLE 344 benzamide (2.51 g) was obtained in the same manner as in Example 186 using 4-amino-3-chlorobenzoic acid (1.71 g), 45 4-(2-Chlorophenyl)-2-ethyl-9-phenyl-6H-thieno3.2-f 3-aminomethyl-4-3-(2-chlorobenzoyl)-5-ethylthiophen-2- 1.2.4 triazolo 4.3-a 14-diazepine (405 mg) and yl)-5-methyl(1,24triazole di-p-toluenesulfonate (7.42 g). p-toluenesulfonic acid monohydrate (570 mg) were dis triethylamine (5.6 ml) and 1-benzotriazolyloxytris solved in a mixed solvent (15 ml) of ethanol and water (9:1), (dimethylamino)phosphonium hexafluorophosphate (Bop and the solution was refluxed for 3 hours. The reaction reagent, 4.64 g). This compound (2.40 g) was dissolved in 50 mixture was concentrated under reduced pressure. The methanol, and methanesulfonic acid (0.302 ml) was added. obtained residue was dissolved in dimethylformamide (10 The reaction mixture was concentrated under reduced ml). Indole-2-carbonyl chloride (293 mg) and triethylamine pressure, and the residue was crystallized from ethyl acetate. (0.7 ml) were added, and the mixture was stirred at room The obtained crude crystals were recrystallized from ethanol temperature for one day. The reaction mixture was parti (30 ml) to give 1.57 g of 4-amino-3-chloro-N-(4-(3-(2- 55 tioned between ethyl acetate and water. The organic layer chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4) was washed with a saturated aqueous sodium hydrogencar triazol-3-ylmethyl)benzamide methan sulfonate. bonate solution and saturated brine, and dried over magne sium sulfate. The solvent was concentrated under reduced m.p. 211-213° C. pressure. The obtained solid was recrystallized from ethyl acetate to give 0.29 g of N-(4-(3-(2-chlorobenzoyl)-5- EXAMPLE 341 ethylthiophen-2-yl)-5-phenyl 1.2.4 triazol-3-ylmethyl) Reaction was carried out in the same manner as in indole-2-carboxamide. Example 186 using trans-3-(2-hydroxyphenyl)propenoic mp. 230°-232° C. acid (1.64 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- ethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- 65 EXAMPLE 345 toluenesulfonate (7.42 g), triethylamine (5.6 ml) and 9-(1-Adamantyl)-4-(2-chlorophenyl)-2-ethyl-6H-thieno 1-benzotriazolyloxytris(dimethylamino)phosphonium 3.2-f 1.24triazolo 4.3-a 14-diazepine (926 mg) and 5,760,032 109 110 p-toluenesulfonic acid monohydrate (1.14 g) were dissolved chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 12.4 in a mixed solvent (25 ml) of ethanol and water (9:1), and triazol-3-ylmethylcarbamoyl)benzoate (1.3 g), and the mix the solution was refluxed for 3 hours. The reaction mixture ture was stirred at room temperature for 2 hours. The was concentrated under reduced pressure, and the obtained reaction mixture was evaporated, and the residue was par residue was dissolved in dimethylformamide (10 ml). titioned between water and ethyl acetate. The aqueous layer Indole-2-carbonyl chloride (585 mg) and triethylamine (1.4 was taken out, and citric acid was added to adjust the ml) were added, and the mixture was stirred at room aqueous solution to pH 3. The solution was extracted with temperature for one day. The reaction mixture was parti ethyl acetate. The organic layer was washed with saturated tioned between ethyl acetate and water. The organic layer brine, and dried over magnesium sulfate. The solvent was was washed with a saturated aqueous sodium hydrogencar O evaporated, and the residue was recrystallized from a mixed bonate solution and saturated brine, and dried over magne solvent of ethyl acetate and diisopropyl ether to give 1.05 g sium sulfate. The solvent was concentrated under reduced of 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- pressure, and the obtained solid was recrystallized from a methyl 124triazol-3-ylmethylcarbamoyl)benzoic acid. mixed solvent of ethyl acetate and methanol to give 0.64 g mp. 133°-136° C. of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-(1- 5 adamantyl) 1.2.4 triazol-3-ylmethyl)indole-2- carboxamide. Production Example 16 mp. 283°-286° C. Methyl 3-(4-(2-chlorophenyl)-9-methyl-6H-thieno3.2-f EXAMPLE 346 1,2,4-triazolo 4.3-a 14-diazepin-2-yl)propionate was 20 prepared by the following method. 1-Dimethylaminoethylindole-2-carboxylic acid (0.55 g) 3-(2-Chlorophenyl)-3-oxo-propionitrile (53.5 g) and sul synthesized by a known method such as the method dis fur (9.5 g) were dissolved in dimethylformamide (120 ml). closed in Japanese Patent Unexamined Publication No. Diethyl 2-(3-oxo-propyl)malonate (71 g) synthesized by the 155871/1993 and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5- method disclosed in J. Am. Chem. Soc. 70,3470 (1948) was ethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- 25 added under ice-cooling, and the mixture was heated at 60 toluenesulfonate (1.76 g) were dissolved in DMF (20 ml). C. for 3 hours. The mixture was poured into ice water (300 Triethylamine (1.33 ml) and Bop reagent (1.05 g) were ml). The mixture was extracted with ethyl acetate to give a added under ice-cooling, and the mixture was stirred at room product. The organic layer was washed 3 times with water temperature. The reaction mixture was partitioned between and dried over magnesium sulfate. The solvent was water and ethyl acetate. The organic layer was washed with 30 evaporated, and isopropyl alcohol was added. The obtained an aqueous citric acid solution, saturated brine, a saturated crystals were collected by filtration to give 78 g of diethyl aqueous sodium hydrogencarbonate solution and saturated 2-(5-amino-4-(2-chlorobenzoyl)thiophen-2-ylmethyl) brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column malonate. chromatography using a mixed solvent of ethyl acetate, 35 Diethyl 2-(5-amino-4-(2-chlorobenzoyl)thiophen-2- methanol and triethylamine as an eluent, and crystallized to ylmethyl)malonate (20 g) and a 4M potassium hydroxide give hydrochloride, whereby 0.27 g of N-(4-(3-(2- aqueous solution (30 ml) were added to ethanol (120 ml), chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl 1.2.4 and the mixture was refluxed under heating for 2 hours. The triazol-3-ylmethyl)-1-(2-dimethylaminoethyl)indole-2- solvent was evaporated, and the residue was dissolved in carboxamide hydrochloride was obtained. water. 1.2M Hydrochloric acid was added to adjust the mp. 213°-215° C. solution to pH 3. The mixture was extracted with ethyl acetate to give a product and the product was washed with EXAMPLE 347 brine, and dried over magnesium sulfate. The solvent was Monomethyl isophthalate (2.86 g) and thionyl chloride evaporated. Dimethylformamide (30 ml) and toluene (70 (12 ml) were added to dichloroethane (30 ml), and the 45 ml) were added to the residue, and the mixture was heated mixture was refluxed with stirring for 5 hours. The solvent at 80° C. for 1 hour. The mixture was washed with water, was evaporated and the residue was dissolved in dimethyl dried over magnesium sulfate and concentrated to give 11.0 formamide (40ml).3-Aminomethyl-4-(3-(2-chlorobenzoyl) g of 3-(5-amino-4-(2-chlorobenzoyl)thiophen-2-yl) -5-ethylthiophen-2-yl)-5-methyl 1.2.4 triazole di-p- propionic acid. toluenesulfonate (10.0 g) and triethylamine (12 ml) were 50 3-(5-Amino-4-(2-chlorobenzoyl)thiophen-2-yl)propionic added under ice-cooling, and the mixture was stirred atroom acid was treated in the same manner as in Production temperature for 2.5 hours. A saturated aqueous sodium Example 10 to give methyl (4-(2-chlorophenyl)-9-methyl hydrogencarbonate solution was added to the reaction mix 6H-thieno 3.2-f 1.24triazolo43-a 14-diazepin-2-yl) ture. The mixture was extracted with ethyl acetate. The propionate. organic layer was washed with an aqueous citric acid 55 solution and saturated brine, and dried over magnesium EXAMPLE 349 sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing Methyl (4-(2-chlorophenyl)-9-methyl-6H-thieno 3.2-f solventiethyl acetate) and recrystallized from a mixed sol 1.2.4 triazolo43-a 14-diazepin-2-yl)propionate (1.0 g) vent of ethyl acetate and diisopropyl ether to give 1.58g of was stirred in 2M hydrochloric acid (12 ml) at 60° C. for 3.5 methyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5- hours. Then, sodium hydrogencarbonate was added to the methyl 124triazol-3-ylmethylcarbamoyl)benzoate. reaction mixture to make the mixture alkaline. Chloroform mp. 111-114 C. and indole-2-carbonyl chloride (0.55 g) were added, and the mixture was stirred at room temperature for 2 hours. An EXAMPLE 348 aqueous citric acid solution was added to adjust the solution Methanol (13 ml) and a 2M sodium hydroxide aqueous to pH 3. The obtained crystals were collected by filtration, solution (2.5 ml) were added to methyl 3-(4-(3-(2- washed with water and ethyl acetate, and dried to give 5,760,032 111 112 3 - (3 - (2 - c hl or o be in Z o y l) - 2 - (3 - ( 2 - EXAMPLE 355 indolecarbonylaminomethyl)-5-methyl 12,4-triazol-4-yl) N-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno 3.2-f 1.2.4 thiophen-5-yl)propionic acid. triazolo 4.3-all 1.4-diazepin-9-ylmethyl)indole-3- m.p. 240° C. (dec.) carboxamide (12 mg) was obtained in the same manner as in Example 61 using 9-aminomethyl-4-(2-chlorophenyl)-2- EXAMPLE 350 ethyl-6H-thieno3.2-fl 1.2.4 triazolo43-a 14-diazepine N-(4-(2-Chlorophenyl)-2-methyl-6H-thieno3.2-f 1.2.4 (1.0 g), indole-3-carboxylic acid (0.49 g), Bop reagent (1.36 triazolo 4.3- a 1,4 diazepin-9-ylmethyl)-3,4- g), triethylamine (0.39 ml) and dimethylformamide (10 ml). dichlorobenzamide (0.45 g) was obtained in the same man 10 mp. 238°-239° C. ner as in Example 59 using 9-aminomethyl-4-(2- chlorophenyl)-2-methyl-6H-thieno3.2-f 1.24triazolo[4, EXAMPLE 356 3-a 1.4 diazepine (0.60 g), dichloroethane (30 ml). triethylamine (0.26 ml) and 3,4-dichlorobenzoyl chloride Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H (0.38 g). thieno3.2-f 1.2.4 triazolo.4.3-a 1.4-diazepin-9-yl) 15 butanoate di-p-toluenesulfonate (3.0 g) and 2-naphthoyl mp. 1939-195° C. chloride (0.73 g) were dissolved in DMF (30 ml). Triethy EXAMPLE 351 lamine (1.46 ml) was added and the mixture was stirred. Water was added to the reaction mixture. The mixture was N-(4-(2-Chlorophenyl)-2,3-dimethyl-6H-thieno3.2-f washed with an aqueous citric acid solution, saturated brine, 1.2.4 triazolo 4.3-a 1.4 diazepin-9-ylmethyl)-3,4- 20 a saturated aqueous sodium hydrogencarbonate solution and dichlorobenzamide (0.43 g) was obtained in the same man saturated brine, and dried over magnesium sulfate. The ner as in Example 59 using 9-aminomethyl-4-(2- solvent was evaporated, and the residue was purified by chlorophenyl)-2,3-dimethyl-6H-thieno 32-f 1.2.4 triazolo silica gel column chromatography using a mixed solvent of 43-a 1,4-diazepine (1.19 g), dichloroethane (60 ml), ethyl acetate and methanol as an eluent to give 1.43 g of triethylamine (0.49 ml) and 3,4-dichlorobenzoyl chloride 25 benzyl (R)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f (0.73 g). 1.2.4 triazolo.43-a 14-diazepin-9-yl)-4-(naphthalene-2- mp. 1939-195° C. carboxamide)butanoate. NMR (270 MHz, DMSO-d):1.04(3H,t.J=7.3 Hz). EXAMPLE 352 30 2.38-2.52(4H.m), 2.66(2H.qJ=7.3 Hz). 5.03-5.11(2H). Benzyl (R)-4-(3.4-dichlorobenzoylamino)-4-(4-(2- 5.68-5.71 (1H.q), 6.36(1Hs), 7.32-795(15Him), 8.40(1H. chlorophenyl)-2-ethyl-6H-thieno3.2-f 124triazolo(43 s), 9.22(1H.s) a 14-diazepin-9-yl)butanoate (4.79 g) was obtained in the same manner as in Example 59 using benzyl (R)-4-amino EXAMPLE 357 4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4) 35 (R)-(-)-4-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f triazolo 4,3-a 1.4 diazepin-9-yl)butanoate di-p- 124triazolo.43-a 14-diazepin-9-yl)-4-(naphthalene-2- toluenesulfonate (8.64 g), 3,4-dichlorobenzoyl chloride carboxamide)butanoic acid (0.32 g) was obtained in the (2.10g), dichloroethane (100 ml) and triethylamine (4.2 ml). same manner as in Example 271 using benzyl (R)-4-(4-(2- NMR (270 MHz, CDC1):1.29(3H,t.J-7.3 Hz), 220-2.70 chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo[4,3- (4H), 2.80(2H.m), 4.63(1H,bs), 5.03(2Hs). 5.18(1H.bs), a 1.4-diazepin-9-yl)-4-(naphthalene-2-carboxamide) 5.94(1H,m), 6.40(1Hs), 720-7.70(11H), 7.90(1H), 8.44 butanoate (1.13 g), methanol (12 ml) and a 2N sodium (1Hm) hydroxide aqueous solution (1.7 ml). NMR (270 MHz. DMSO-d):1.06(3H.t.J=7.5 Hz). EXAMPLE 353 2.31-2.54(4H.m), 2.71(2H.q.J=7.5 Hz). 4.86(2H). N-(4-(2-Chlorophenyl)-2-propyl-6H-thieno32-f 12.4 45 5.66-5.68(1H,q), 6.37(1H,s), 7.31–798 (10H,m), 8.40(1H, triazolo 4.3-a 1.4 diazepin-9-ylmethyl)-3,4- s), 9.22(1H.s) dichlorobenzamide (0.56 g) was obtained in the same man ot-101.4 (c=1, dimethylformamide) ner as in Example 59 using 9-aminonethyl-4-(2- chlorophenyl)-2-propyl-6H-thieno3,2-f 12.4 triazolo.4. EXAMPLE 358 50 3-a 1.4 diazepine (2.81 g), dichloroethane (50 ml), Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H triethylamine (1.11 ml) and 3,4-dichlorobenzoyl chloride thieno,3,2-f 1.2.4 triazolo.4.3-a 1.4)diazepin-9-yl) (1.66 g). butanoate di-p-toluenesulfonate (3.0 g) and NMR (270 MHz, DMSO-d):0.76(3H,t.J-7.3 Hz), 1.47 2-naphthalenesulfonyl chloride (0.87 g) were dissolved in (2HJ=7.3 Hz). 2.68(2H.t.J=7.3 Hz), 4.88-4.90(4H.m). 6.38 55 DMF (30 ml). Triethylamine (1.46 ml) was added and the (1Hs), 7.39-8.04(7Him), 9.23-9.27(1H,t) mixture was stirred. Water was added to the reaction mix ture. The mixture was washed with an aqueous citric acid EXAMPLE 354 solution, saturated brine, a saturated aqueous sodium hydro N-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24) gencarbonate solution and saturated brine and dried over triazolo 4.3-a 1.4diazepin-9-ylmethyl)guinoline-3- magnesium sulfate. The solvent was evaporated, and the carboxamide (0.59 g) was obtained in the same manner as in residue was purified by silica gel column chromatography Example 61 using 9-aminomethyl-4-(2-chlorophenyl)-2- using ethyl acetate as an eluent to give 1.25 g of benzyl ethyl-6H-thieno3.2-f 1.2.4 triazolo43-a 14-diazepine (R)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.24) (1.0 g), 3-quinolinecarboxylic acid (0.53 g), Bop reagent triazolo 4.3-a) 1,4-diazepin-9-yl)-4-(naphthalene-2- (1.36 g), triethylamine (0.78 ml) and dimethylformamide 65 sulfonamide)butanoate. (10 ml). NMR (270 MHz, DMSO-d): 1.13(3H,t.J=7.5 Hz), mp. 2009-202° C. 2.07-2.39(4H.m). 2.70(2H.q.J=7.5 Hz), 4.68(2H). 5,760,032 113 114 4.68-4.94(2H.q), 4.97-5.02(1H,q), 6.44(1H,s), 7.21-7.98 (R)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 12.4 (12H.m), 8.00-8.03(3H,t). 8.31 (1H,s), 8.81-8.83(1H,s) triazolo 4.3-a 14-diazepin-9-yl)-4-(3-(2-methoxyphenyl) ureido)butanoate. EXAMPLE 359 mp. 179°-181° C. (R)-(-)-4-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f EXAMPLE 363 1.2.4 triazolo.43-a 14-diazepin-9-yl)-4-(naphthalene-2- (R)-(-)-4-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f sulfonamide)butanoic acid (0.50 g) was obtained in the same 1.2.4 triazolo 4.3-a 1,4-diazepin-9-yl)-4-(3-(2- manner as in Example 271 using benzyl (R)-4-(4-(2- methoxyphenyl)ureido)butanoic acid (0.17 g) was obtained chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo.43 in the same manner as in Example 271 using benzyl (R)-4- a 1,4-diazepin-9-yl)-4-(naphthalene-2-sulfonamide) 1O (4-(2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo butanoate (1.07 g), methanol (10 ml) and a 2N sodium 43-a 1.4-diazepin-9-yl)-4-(3-(2-methoxyphenyl)ureido) butanoate (0.7 g), methanol (10 ml) and a 1N sodium hydroxide aqueous solution (1.5 ml). hydroxide aqueous solution (1.05 ml). m. p. 227-229 C., o=-26.8 (c= 1, NMR (270 MHz. CDC1):1.25(3H.t.J=7.4 Hz). 2.31-2.52 dimethylformamide) 15 (4H.m), 2.77(2H.qJ=7.4 Hz), 3.72(3H.s). 4.65-5. 13(2H,d). 5.86-5.89(1H,q), 6.36(1H,s), 6.71-8.13(10H,m) EXAMPLE 360 EXAMPLE 364 Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H Benzyl alcohol (2.8 ml) was added to a solution of thieno3.2-f 1,2,4-triazolo 4.3-a) (1.4diazepin-9-yl) D-O-aminoadipic acid (4.0 g) in 60% sulfuric acid (3.24 mi), butanoate di-p-toluenesulfonate (3.0 g) and 2-chlorophenyl and the mixture was heated at 70° C. for 1 hour. The reaction isocyanate (0.46 ml) were dissolved in DMF (30 ml). mixture was concentrated under reduced pressure to remove Triethylamine (1.46 ml) was added and the mixture was moisture. The reaction mixture was added to ice water (300 stirred and water was added to the reaction mixture. The ml) containing sodium hydrogen-carbonate (4.58 g) to give mixture was washed with an aqueous citric acid solution, 25 8-benzyl D-O-aminoadipate (2.09 g). 8-Benzyl D-O- saturated brine, a saturated aqueous sodium hydrogencar aminoadipate (2.47 g) and triethylamine (2.06 ml) were bonate solution and saturated brine, and dried over magne mixed with water (15 ml). A solution of tert-butyl dicarbon sium sulfate. The solvent was evaporated, and the residue ate (2.36 g) in dioxane (15 ml) was added, and the mixture was purified by silica gel column chromatography using was stirred at room temperature for 7 hours. Water (50 ml) ethyl acetate as an eluent to give 2.02 g of benzyl (R)-4-(4- 30 was added to the reaction mixture and the mixture was (2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo.4, washed with ethyl acetate (50 ml). Citric acid was added to 3-a) (1,4)diazepin-9-yl)-4-(3-(2-chlorophenyl)ureido) make the mixture acidic. The mixture was extracted with butanoate. ethyl acetate. The extract was dried over magnesium sulfate. NMR (270 MHz, DMSO-d): 1.16(3H,t.J=7.4 Hz). The solvent was evaporated to give 2.93 g of 8-benzyl 2.15-2.26(4H.m), 2.78(2H,q.J=7.4 Hz), 4.79(2H), 35 N-O-tert-butoxycarbonylamino-D-adipate. 5.01-5.11(1H.q), 5.43-5.51(1H.q), 6.46(1Hs), 6.94-8.15 Benzyl (R)-(-)-5-(3,4-dichlorobenzoylamino)-5-(4-(2- (15H,m) chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo43 a 1.4-diazepin-9-yl)pentanoate (0.47 g) was obtained in the EXAMPLE 361 same manner as in Example 270 using 8-benzyl N-o-tert (R)-(-)-4-(4-(2-Chlorophenyl)-2-ethyl-6H-thieno3.2-f butoxycarbonylamino-D-adipate (2.93 g) thus obtained, tet 1.2.4 triazolo 4.3-a 1,4diazepin-9-yl)-4-(3-(2- rahydrofuran (30 ml), triethylamine (1.3 ml), isobutyl chlo chlorophenyl)ureido)butanoic acid (0.25 g) was obtained in roformate (1.2 ml) and 5-(2-chlorophenyl)-7-ethyl-2- the same manner as in Example 271 using benzyl (R)-4-(4- hydrazine-3H-thieno 2,3-e 14 diazepine (2.66 g). (2-chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo4. NMR (270 MHz. CDC1):1.29(3H.t.J=73 Hz), 1.70-2.41 3-a 1.4-diazepin-9-yl)-4-(3-(2-chlorophenyl)ureido) 45 (6H.m), 2.80(2H.qJ=7.3 Hz), 4.62-5.19(2H,d), 5.04(2H.s), butanoate (0.5 g), methanol (15 ml) and a N sodium 5.80-5.88(1H,q), 6.39(1Hs), 7.23-7.87(12Him), 8.59(1H, hydroxide aqueous solution (0.755 ml). d) NMR (270 MHz, DMSO-d): 1.18(3H,t.J=7.5 Hz), O)=-61.6° (c=1, chloroform) 2.06-2.33(4H.m), 2.80(2H,q.J=7.5 Hz), 4.83 (2H), EXAMPLE 365 5.41-5.45(1H,q), 6.45(1H,s), 6.93-8.13(10H.m) (R)-(-)-5-(3,4-Dichlorobenzoylamino)-5-(4-(2- (O-53.6° (c=1, dimethylformamide) chlorophenyl)-2-ethyl-6H-thieno3.2-f 1.2.4 triazolo43 a 14-diazepin-9-yl)pentanoic acid (72 mg) was obtained EXAMPLE 362 in the same manner as in Example 271 using benzyl (R)-(-)- 55 5-(3,4-dichlorobenzoylamino)-5-(4-(2-chlorophenyl)-2- Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H ethyl-6H-thieno 3.2-f 1.24)triazolo 4.3-a 1.4-diazepin thieno3.2-fl 1.2.4 triazolo 4.3-a 1.4)diazepin-9-yl) 9-yl)pentanoate (0.41 g), methanol (10 ml) and a 1N sodium butanoate di-p-toluene sulfonate (2.0 g) and hydroxide aqueous solution (1.16 ml). 2-methoxyphenyl isocyanate (0.34 ml) were dissolved in NMR (270 MHz. DMSO-d):1.33(3H.t.J=7.5 Hz). DMF (20 ml). Triethylamine (0.97 ml) was added and the 1.74-2.60(6H.m), 2.86(2H.qJ=7.5 Hz), 4.77-5.03(2H,d), mixture was stirred. Water was added to the reaction mix 5.96-6.02(1H,t), 6.44(1Hs), 7.24-8.14(7Him), 9.41-9.34 ture. The mixture was washed with an aqueous citric acid (1H,d) Solution, saturated brine, a saturated aqueous sodium hydro (o)=-87.5° (c=1, dimethylformamide) gencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the 65 EXAMPLE 366 residue was purified by silica gel column chromatography N-(4-(3-Chlorophenyl)-2-methyl-6H-thieno3.2-f 12.4 using ethyl acetate as an eluent to give 1.19 g of benzyl triazolo 4,3-all 1.4 diazepin-9-ylmethyl)-3,4- 5,760,032 115 116 dichlorobenzamide is obtained in the same manner as in mixed solvent of methanol and water (9:1). Example 59 using 9-aminomethyl-4-(3-chlorophenyl)-2- p-Toluenesulfonic acid monohydrate is added, and the mix methyl-6H-thieno3.2-f 1.2.4 triazolo.4.3-a 1.4 ture is refluxed under heating for 3 hours. The solvent is diazepine, dichloroethane, triethylamine and 3,4- evaporated. Dimethylformamide, 3-methoxyphenyl isocy dichlorobenzoyl chloride. anate and triethylamine are added, and the mixture is stirred for 1 hour to give N-(4-(3-(2-chlorobenzoyl)-5- EXAMPLE 367 isopropylthiophen-2-yl)-5-methyl 12.4 triazol-3- N-(4-(3-Chlorophenyl)-2-ethyl-6H-thieno3,2-f 1.24) ylmethyl)-N'-(3-methoxyphenyl)urea. triazolo 4,3-a 1,4 diazepin-9-ylmethyl)-N'-(2- methoxyphenyl)urea is obtained in the same manner as in 1O EXAMPLE 373 Example 64 using 9-aminomethyl-4-(3-chlorophenyl)-2- 4-(2-Chlorophenyl)-2-cyclopropyl-9-methyl-6H-thieno ethyl-6H-thieno3.2-f 1.2.4 triazolo43-a 14-diazepine, 3.2-f 1,2,4-triazolo 4,3-a) 1,4-diazepine is dissolved in a 2-methoxyphenyl isocyanate and chloroform. mixed solvent of methanol and water (9:1). p-Toluenesulfonic acid monohydrate is added, and the mix EXAMPLE 368 15 ture is refluxed under heating for 3 hours. The solvent is 4-(2-Chlorophenyl)-9-methyl-2-propyl-6H-thieno3.2-f evaporated. Dimethylformamide. 3-methoxyphenyl isocy 1.2.4 triazolo43-a 14-diazepine is dissolved in a mixed anate and triethylamine are added, and the mixture is stirred solvent of methanol and water (9:1). p-Toluenesulfonic acid for 1 hour to give N-(4-(3-(2-chlorobenzoyl)-5- monohydrate is added, and the mixture is refluxed under cyclopropylthiophen-2-yl)-5-methyl 1,2,4-triazol-3- heating for 3 hours. The solvent is evaporated. ylmethyl)-N'-(3-methoxyphenyl)urea. Dimethylformamide, indole-2-carbonyl chloride and tri ethylamine are added, and the mixture is stirred for 1 hour EXAMPLE 374 to give N-(4-(3-(2-chlorobenzoyl)-5-propylthiophen-2-yl)- (4-(2-Chlorophenyl)-9-methyl-6H-thieno3.2-f 1.24) 5-methyl(1,2,4-triazol-3-ylmethyl)indole-2-carboxamide. 25 triazolo 4.3-a 1.4-diazepin-2-yl)carboxylic acid and p-toluenesulfonic acid are dissolved in a mixed solvent of EXAMPLE 369 methanol and water (9:1), and the solution is refluxed for 3 hours. The solvent is evaporated. The residue is dissolved in 4-(2-Chlorophenyl)-2-isopropyl-9-methyl-6H-thieno3, dimethylformamide. 3-Chlorophenyl isocyanate and triethy 2-fl 1.2.4 triazolo43-a 14-diazepine is dissolved in a 30 lamine are added under ice-cooling, and the mixture is mixed solvent of methanol and water (9:1). stirred for 1 hour to give (3-(2-chlorobenzoyl)-2-(3-(3-(3- p-Toluenesulfonic acid monohydrate is added, and the mix chlorophenyl)ureidomethyl)- 5-methyl(1,24triazol-4-yl) ture is refluxed under heating for 3 hours. The solvent is evaporated. Dimethylformamide, indole-2-carbonyl chlo thiophen-5-yl)carboxylic acid. ride and triethylamine are added, and the mixture is stirred for 1 hour to give N-(4-(3-(2-chlorobenzoyl)-5- 35 EXAMPLE 375 isopropylthiophen-2-yl)-5-methyl(1,2,4-triazol-3-ylmethyl) N-(4-(2-Chlorophenyl)-2-propyl-6H-thieno3,2-f 12.4 indole-2-carboxamide. triazolo (4,3-a 1.4)diazepin-9-ylmethyl)indole-2- carboxamide is obtained in the same manner as in Example EXAMPLE 370 59 using 9-aminomethyl-4-(2-chlorophenyl)-2-propyl-6H 4-(2-Chlorophenyl)-2-cyclopropyl-9-methyl-6H-thieno thieno 3.2-fl 1.2.4 triazolo 4.3-a 1.4-diazepine. 3.2-f 1,2,4-triazolo(4.3-a 14-diazepine is dissolved in a dimethylformamide, triethylamine and indole-2-carboxylic mixed solvent of methanol and water (9:1). acid chloride. p-Toluenesulfonic acid monohydrate is added, and the mix EXAMPLE 376 ture is refluxed under heating for 3 hours. The solvent is 45 evaporated. Dimethylformamide, indole-2-carbonyl chlo N-(4-(2-Chlorophenyl)-2-isopropyl-6H-thieno3.2-f ride and triethylamine are added, and the mixture is stirred 1,2,4-triazolo4.3-a 1.4-diazepin-9-ylmethyl)indole-2- for 1 hour to give N-(4-(3-(2-chlorobenzoyl)-5- carboxamide is obtained in the same manner as in Example cyclopropylthiophen-2-yl)-5-methyl(1,2,4-triazol-3- 59 using 9-aminomethyl-4-(2-chlorophenyl)-2-isopropyl ylmethyl)indole-2-carboxamide. 50 6H-thieno3.2-f 1.2.4 triazolo 4.3-a 14-diazepine, dimethylformamide, triethylamine and indole-2-carboxylic EXAMPLE 371 acid chloride. 4-(2-Chlorophenyl)-9-methyl-2-propyl-6H-thieno3.2-f EXAMPLE 377 124triazolo43-a 14-diazepine is dissolved in a mixed solvent of methanol and water (9:1). p-Toluenesulfonic acid 55 N-(4-(2-Chlorophenyl)-2-cyclopropyl-6H-thieno3.2-f monohydrate is added, and the mixture is refluxed under 1.2.4 triazolo.43-a) (1.4ldiazepin-9-ylmethyl)indole-2- heating for 3 hours. The solvent is evaporated. carboxamide is obtained in the same manner as in Example Dimethylformamide, 3-methoxyphenyl isocyanate and tri 59 using 9-aminomethyl-4-(2-chlorophenyl)-2-cyclopropyl ethylamine are added, and the mixture is stirred for 1 hour 6H-thieno3.2-f 1.2.4 triazolo.4.3-a 14-diazepine, to give N-(4-(3-(2-chlorobenzoyl)-5-propylthiophen-2-yl)- dimethylformamide, triethylamine and indole-2-carboxylic 5-methyl(1,2,4-triazol-3-ylmethyl)-N'-(3-methoxyphenyl) acid chloride. EXAMPLE 378 EXAMPLE 372 55 N-(2-Chlorophenyl)-N'-(4-(2-chlorophenyl)-2-propyl 4-(2-Chlorophenyl)-2-isopropyl-9-methyl-6H-thieno3. 6H-thieno 3.2-f 1.2.4 triazolo 4.3-a 1,4-diazepin-9- 2-f 1.2.4 triazolo43-a 1.4-diazepine is dissolved in a ylmethyl)urea is obtained in the same manner as in Example

5,760,032 119 120

TABLE I-1

Ar

H-3Y - Z1 R S

- N . Example No. R2 R. R. Air y 21 1 CH. H. H. -NHCO- O C

2 C.H. H. H. -NHCO- C1 C ICC

3 CH H H -NHCO- CO Cl

4 C.H. H. H -NCO

Cl

-NHCO

" N ) H -NHCO"O CH -NHCo

COOB

-NCO

Cl N O CHCOOEt

-NHCO

C N O CHCOOH 5,760,032 122

TABLE I-1-continued

Air

R3 CH-Y-Z1 N R S -(W -‘s N 1 N Example No. R. R Air Y Z

iO CH CH -NHCO-cer

C

TABLE I-2

Example No. R2 R7 Ar Y Z. 11 CH CH, -NHCO

C

12 CHs CH -NHCO

Cl

3. C2Hs CH, -NHCO

C

14 CH CH -NECO

C N H 15 CH CH -NHCO -

C1 N H 16 CH CH Cl 5,760,032 123 124

TABLE I-2-continued

N Example No. R. R R7 Ar Y Z 17 C.H. H CH, -NHCO

C CHCOO-tBu 18 CH H CH -NHCO- C

C CHCOOEt 19 C.H. H. CH -NHCO- C

C CHCOOH 2O C.H. H. CH -NHCO

C O

Example No. R. R R. R. Ar Y 21 2 H C.H. H. CH -NHCO- u? Cl

22 H CHs H CH -NHCONH- O

C1

-NECONH

Cl C1 C 5,760,032 125 126

TABLE I-3-continued

Example No. R. R R. R. Air Y Zl 24 H CH H CH ca."-NHCONH C. 25 H C.H., H CH c. n-NHCONH- c. Cl 26. H CH H CH Cl, -NHCONH 1C. 27 H. C.H. H. CH Cl, -NHCONH 1C. 28 CH, CH, H CH, Cl, -NHCONH 1C. 29 (CHs) H CH, C, -NHCONH O. 30 H C.H. H. H c. -NHCONH O

5,760,032 129 130

TABLE I-4-continued

40 CH H CF, -NHCO- Cl

C C1

Example No. R. R. R. Air Y Z

Cl C 42 CH H CF Cl Cl 43 CH H CF,

45 C.H. H. (CH)COEt -NHCO- C Cl C C. 46 CH H (CH)COH -NHCO- C1 Cl Cl C1 5,760,032 131 132

TABLE I-5-continued

Example No. R. R. R. Ar Y Z 47 CHs H (CH),COH -NHCO all- C

C N H

48 CHs H H -NHSO,- CO C

49 CHs H CH -NHSO,- CO Cl

50 C.H. H. CH - OCONH- O

C C

Example No. R. R R Air Y Z 51 CH, H CH,

C C

52 CH H CH, - OCONH- C

C

as OCONHe

C Hs 5,760,032 133 134

TABLE I-6-continued

Example No. R. R. R. Ar Y Z 54 C.H. H. CH, - OCONH- C

Cl CH3

55 CH H CH - OCONH- O

C

56 CH H CH - OCONH

Cl OCH

57 CHs H CH - OCO- O

Cl Cl

58 C.H. H. CH - OCO

C1 N H

71 CH. H. Br -NHCO- Cl C C.

72 C.H. H. Br -NHCO- C

C N H

5,760,032 137 138

TABLE I-7-continued

Example No. R2 R R7 Ar Y Z1 174 CH. H CH -NHCO- Cl

Cl

TABLE I-8

Example No. R. R. R. Air Y Zl 81 CH. H. H. -NHCO- Cl Cl Cl C C 82 CH. H. H -NHCO Cl C1 83 CH. H. H. -NHCO Cl C1 CHCOOEt

85 CHs H H -NHCONH- Cl Cl C OCH 86 C.H. H. H. -NHCONH Cl Cl CI C 5,760,032 139 140 TABLE I-8-continued

87 CH, H H -NHCONH

C1 CH

TABLE I-9 AT

H3 Y Zi R S N -K N N

Example No. R. R Ar Y Zl 88 C.H. H. -NHCO- Cl

C 1

-NHCO

Cl N O H -NHCO

Cl J.ON CHCOOEt 91 CH. H -NHCO- C

C CHCOOH 92 C.H. H -NHCONH- Cl Cl OCH3 93 CH, H -NHCONH- O

C C 5,760,032 141 142

TABLE I-9-continued

Air O R3 | | CH-Y-Z1 R S 'N / W N SN 1 N

Example No. R. R Air Y Z

94 CH, H -NHCONH

C CH

TABLE I-10

Example No. R? R. R. Ar Y Z1 175 CH H CH, -NHCO

Cl Cl

176 CH. H. CH

C1

177 CH H CH, Br

Cl

178 CH H CH,

Cl Br

179 CH H CH

C

180 CH H CH

Cl 5,760,032 143 144

TABLE I-10-continued

Example

181 CH H CH, -NHCO

Cl N O CHCHCOOMe 182 CH H CH -NHCO Cl, N CHCHCOOH 183 CH H CH, -NHCO C1

Cl N H 184 CH H CH, -NCO- F C Cl N H

TABLE I-11 AT O R3 R | | CH-Y-Z1 S N W -S N 1 N Example No R2 R R Ar Y zi 185 C.H. H CH, -NHCO- OCH3

C N H 186 CH. H. CH, -NHCO

Cl N

187 CH, H CH, -NHCO

Cl O 5,760,032 145 146

TABLE I-11-continued

Example No. R2 R R Air Y Z 188 CH H CH C. -NHCO J. C. 189 C.H. H. CH, co-NHCONH 190 CH H CH C. -NHCONH- C. CH3 191 CH H CH Cl, -NHCONH ... O 192 C.H. H. CH, c -NHCONH- c. OCH 193 CH H CH -NHCONH Cl C ACl CHCOO-tBu 194 CH H CH Cl, -NHCONH O. 5,760,032 147 148

TABLE I-12

Example No. R. R R7 AT Y Z. 195 CH. H. CH -NHSO- C C

Cl C

196 CH. H. CH -NHCSNH O

C

197 CH, H CH, -NHCO- Cl Cl C C 198 CH, H CH -NHCO- C

Cl N H

199 CH, H CH -NHCO

Cl CHCOOEt 200 CH, H CH -NHCO- c C1 N CHCOOH 201 CH, H CH, -NHCON- O

Cl C

202 CH, H CH -NHCONH- ICl Cl CH3

203 CH, H CH -NHCONH- Cl

Cl OCH 5,760,032 149 150

TABLE I-12-continued

Example No. R. R. R. Air Y Zi 204 H H CH -NHCO- C

Cl C1

TABLE I-13

N 1 Example No. R. R2 R3 R7 Ar Y Z 205 H H H CH, NHCO C

Cl N H 206 H H H CH -NHCO

C CHCOOEt 2O7 H H H CH, -NHCO- c

C1 CHCOOH 208 H H H CH -NHCONH- O

C C

209 H H H CH, -NHCONH

C CH

210 H H H CH, -NHCONH

C1 OCH 5,760,032 151 152

TABLE I-13-continued

211 CH, CH, H CH, C. -NHCO- C.C 212 CH CH, H CH Cl, -NHCO 213 CH, CH H CH -NHCO

Cl CHCOOEt 214 CH, CH, H CH, -NHCO- C Cl N

CHCOOH

No. R' R2 R. R7 Air Y Z 215 CH, CH, H CH, -NHCONH

C C

216 CH, CH, H CH -NHCONH

C1 CH3

217 CH, CH, H CH, -NHCONH

Cl OCH 5,760,032 153 154

TABLE I-4-continued

Example No. R. R R R Air Y Zl

28 H CHs H CH -NHCO- C Cl

C

219 H CHs H CH, -NCO - c

N H 220 H CHs H CH, -NHCO- D

CHCOOE

221 H CHs H CH, -NHCO as C

N CHCOOH

222 H CHs H CH -NHCONH- O

C

223 H CHs H CH -NHCONH- -Cl CH

224 H CH H CH -NHCONH- ICl

OCH 5,760,032 1SS 156

TABLE I-15

Example No. R2 R3 R Air Y Zl 225 CH H CH, -NCO- C C

F Cl

226 CH H CH -NCO- C

F N H 227 CH H CH, -NHCO

R CHCOOEt 228 CH H CH, -NHCO C F N CHCOOH 229 CH, H CH, -NHCONH- O

F C

230 CH H CH -NHCONH- JCl

F CH

231 CHs H CH -NHCONH- Cl

F OCH

232 CHs H CHNOMe) -NHCO- Cl C C

233 CH H CHNOMe) Cl -NHCO ur C 5,760,032 157 158

TABLE I-15-continued

CHCOOEt

TABLE - 16 Air O R R | | CH-Y-Z1 S N W -S N 1 N Example No. R2 R3 R Ar Y Z1 235 C.H. H CHNOMe), -NHCO in

C1 CHCOOH 236 CH H CHNOMe) -NHCONH- O

C C 237 CH H CHNOMe) -NHCONH- Cl

C CH 238 CH H CHNOMe) -NHCONH- Cl

C OCH

239 CH H CHCCH) -NHCO- C1

C al C1 240 CH H CHCCH) -NHCO- C

C N H 5,760,032 159 160

TABLE I-16-continued

Example No. R. R. R. Ar Y Z 241 CH H CHCH), -NHCO- C C N CHCOOEt 242 CH H CHCCH) -NHCO- C

C1 CHCOOH 243 CH H CH(CH) -NHCONH- O

Cl C

244 CH H CHCCH) -NHCONH- ICl

C CH

TABLE -17 Air O R3 CH-Y-Z R S N W -‘s N1 N Example No. R. R. R. AT Y Zi 245 C.H. H CH(CH) -NHCONH

Cl OCH

246 COOEt H CH -NHCO- Cl

Cl Cl

247 COOEt H CH, -NHCO

Cl N H 5,760,032 161 162

TABLE I-17-continued

Example No. R2 R3 R Air Y Zl 248 COOEt H CH, -NHCONH- c

C C

249 COOEt H CH, -NHCONH-so C

C CH

250 COOEt H CH, -NHCONH

C OCH

25 COOH. H. CH -NHCO- C Cl C.

252 COOH. H. CH -NHCO

Cl N H

253 COOH. H. CH -NHCONH- IO

Cl C

254 COOH. H. CH, Cl -NHCONH Cl ICl CH 5,760,032 163 164

TABLE I-18

Example No. R. R R7 Air Y Z 2S5 COOH H CH -NHCONH- |Cl

Cl OCH

256 CHCOOMe H CH -NHCO- C1 C1 C.

257 CHCOOMe H CH -NHCO

C N H 258 CHCOOMe H CH, -NHCONH- O

C C 259 CHCOOMe H CH, -NHCONH- Cl

C CH3 260 CHCOOMe H CH -NHCONH- Cl

C1 OCH

261 CHCOOH H CH -NCO- C C1 JC 262 CHCOOH H CH -NHCO- C

C1 N H 263 CHCOOH H CH -NHCONH- O

C C

264 CHCOOH H CH Cl -NHCONH -Cl CH

5,760,032 175 176

TABLE I-22-continued

Air O R3 CH-Y-Z1 R S N - -‘s N 1 N Example No. R. R. R.? Air Y Z 322 CH H CH, -NHCo- HC

Cl

(CH2)3COOH

TABLE I-23

Example No. R2 R3 R Air Y Z. 323 CH, CHCOOEt CH, O C1 324 CH, CHCOOH CH

Cl C1

325 CH, CHCOOEt CH, -NCO

326 CH, CHCOOH CH, -NHCO

C

327 CH (CH2)COOEt CH, -NHCO- C

C O C 328 CH (CHCOOH CH,

C Cl 5,760,032 177 178

TABLE I-23-continued

Example No. R? R R? Air 329 CH (CH)COOEt CH -NHCO

N C. H C. 330 CH (CH)COOH CH, -NHCO

N C. H C. 331 C.H. H. CH -NHCO

Cl N O CH: 332 CH. H. CH -NHCO- C Cl N CH:

TABLE I-24 Ar O R3 R CH-Y-2 S N W -S N 1 N Example No. R. R. R. Air Y Z. 333 C.H. H CH -NHCO- EtOOC C C CH 334 CH H CH -NHCO- t-BOOC

C

CH2

5,760,032 183 184

TABLE I-26

Ar

R S -K -S N Y N

Example No. R. R. R. Ar Y Zi 368 CH H CH -NHCO- C

C N H 369 CHCH.) H CH -NCO- C

C1 N H 370 C H CH, -NHCO- C

C N H

371 CH, H CH -NHCONH- Cl

C OCH3

372 CHCH.) H CH -NHCONH- Cl

C OCH

373 C H CH -NHCONHo- Cl C1 OCH

34 COOH H CH -NHCONH- Cl

Cl C